NAKANISHI Isao

Researcher Information

URL

http://kaken.nii.ac.jp/d/r/10362576.ja.html

J-Global ID

• 201401086004316207

Research Interests

• フラグメント分子軌道法   FKBP   溶媒和カネルギー   SBDD   結合エネルギー   医薬分子設計   HIV-1プロテアーゼ   HIV-1   自由エネルギー摂動法   タンパク質   溶媒和エネルギー   構造最適化   結合自由エネルギー   熱力学積分法   水和エネルギー   生体高分子   量子・古典融合法   分子シミュレーション   電子状態計算   FMO法   溶媒の連続誘電体モデル   電子状態計算法   

Research Areas

• Life sciences / Pharmaceuticals - chemistry and drug development
• Nanotechnology/Materials / Basic physical chemistry

Academic & Professional Experience

• 2008/04 - Today  Kindai UniversityFaculty of Pharmacy教授
• 2003/08 - 2008/03  Kyoto University薬学部助教授/准教授
• 1985/04 - 2003/07  藤沢薬品工業（株）

Education

• 1983/04 - 1985/03  大阪大学大学院  薬学研究科  薬品化学専攻
• 1979/04 - 1983/03  Osaka University  School of Pharmaceutical Sciences  製薬科学科

Association Memberships

• JAPANESE SOCIETY FOR CHEMICAL BIOLOGY   THE CHEM-BIO INFORMATICS SOCIETY   THE PHARMACEUTICAL SOCIETY OF JAPAN   

Published Papers

• Enhanced inhibitory activity of compounds containing purine scaffolds compared to protein kinase CK2α considering crystalline water

  Keiji Nishiwaki; Shiori Nakatani; Shinya Nakamura; Kenji Yoshioka; Eri Nakagawa; Masato Tsuyuguchi; Takayoshi Kinoshita; Isao Nakanishi

  RSC Medicinal Chemistry Royal Society of Chemistry (RSC) 2024 

  We recently reported novel purine-based CK2α inhibitors using the solvent ordering–based method as virtual screening. Among these, the X-ray crystal structure of a complex with CK2α was determined. The results...
• Role of the thiosugar ring in the inhibitory activity of salacinol, a potent natural α-glucosidase inhibitor

  Katsuki Takashima; Shinya Nakamura; Maiko Nagayama; Shinsuke Marumoto; Fumihiro Ishikawa; Weijia Xie; Isao Nakanishi; Osamu Muraoka; Toshio Morikawa; Genzoh Tanabe

  RSC Advances Royal Society of Chemistry (RSC) 14 (7) 4471 - 4481 2024 

  In contrast to previous SAR studies of aza-compounds (23vs.24 and 25), the present study using analogues (26a–26c, 27c, and 28a–28c) of salacinol (1) revealed an essential role of the thiosugar ring in effectively inhibiting α-glucosidase.
• Design, Synthesis and Structure–Activity Relationship Studies of Protein Kinase CK2 Inhibitors Containing a Purine Scaffold

  Keiji Nishiwaki; Shinya Nakamura; Kenji Yoshioka; Eri Nakagawa; Shiori Nakatani; Masato Tsuyuguchi; Takayoshi Kinoshita; Isao Nakanishi

  Chemical and Pharmaceutical Bulletin Pharmaceutical Society of Japan 71 (7) 558 - 565 0009-2363 2023/07 

  Protein kinase CK2 (CK2) is a target protein for the development of therapeutic drugs for cancer, nephritis, COVID-19 infection, etc. We have previously identified new candidate CK2α inhibitors containing a purine scaffold using the SDO-VS method. Docking calculations suggest that compound 11 binds CK2 eliminating the water molecule observed in many CK2-CK2 inhibitor complex crystal structures, as evidenced by X-ray crystallography results. Compound 12, which was designed from structure-activity relationship data, showed an IC50 of 4.3 μM.
• Spectral and theoretical analysis of derivatives of 1,2,3,3-tetramethyl-3H-indolium iodide (TMI), a highly selective derivatization reagent of cyanide, and their utility for the analysis of cyanide concentrations in beverages

  Keiji Nishiwaki; Yasuhiro Morikawa; Shigeo Suzuki; Kazutaka Shiomi; Isao Nakanishi

  Analytical Sciences Springer Science and Business Media LLC 0910-6340 2023/06
• Fragment Molecular Orbital based affinity prediction toward pyruvate dehydrogenase kinases: Insights into the charge transfer in hydrogen bond networks

  Tatsuo Akaki; Shinya Nakamura; Keiji Nishiwaki; Isao Nakanishi

  Chemical and Pharmaceutical Bulletin Pharmaceutical Society of Japan 71 (4) 299 - 306 0009-2363 2023/02 [Refereed]
  
• System truncation accelerates binding affinity calculations with the fragment molecular orbital method: A benchmark study

  Shinya Nakamura; Tatsuo Akaki; Keiji Nishiwaki; Midori Nakatani; Yuji Kawase; Yuki Takahashi; Isao Nakanishi

  Journal of Computational Chemistry Wiley 44 (7) 824 - 831 0192-8651 2022/11 [Refereed]
  
• Bivalent binding mode of an amino-pyrazole inhibitor indicates the potentials for CK2α1-selective inhibitors.

  Asaka Ikeda; Masato Tsuyuguchi; Daisuke Kitagawa; Masaaki Sawa; Shinya Nakamura; Isao Nakanishi; Takayoshi Kinoshita

  Biochemical and biophysical research communications 630 30 - 35 2022/11 

  Casein kinase 2 (CK2) is a vital protein kinase that consists of two catalytic subunits (CK2α1 and/or CK2α2) and two regulatory subunits (CK2β). CK2α1 is a drug target for nephritis and cancers, while CK2α2 is a serious off-target because its inhibition causes testicular toxicity. High similarity between the isozymes CK2α1 and CK2α2 make it difficult to design CK2α1-specific inhibitors. Herein, the crystal structures of CK2α1 and CK2α2 complexed with a 3-amino-pyrazole inhibitor revealed the remarkable differences in the protein-inhibitor interaction modes. This inhibitor bound to the ATP binding sites of both isozymes in apparently distinct orientations. In addition, another molecule of this inhibitor bound to CK2α1, but not to CK2α2, at the CK2β protein-protein interface. Binding energy calculations and biochemical experiments suggested that this inhibitor possesses the conventional ATP-competitive characteristics with moderate allosteric function in a molecular glue mechanism. These results will assist the potential design of potent and selective CK2α1 inhibitors.
• Determination of cyanide in blood by GC–MS using a new high selectivity derivatization reagent 1,2,3,3-tetramethyl-3H-indolium iodide

  Yasuhiro Morikawa; Keiji Nishiwaki; Shigeo Suzuki; Kazutaka Shiomi; Isao Nakanishi

  Forensic Toxicology Springer Science and Business Media LLC 40 (2) 393 - 399 1860-8965 2022/07
• Development of a cost-effective laser diode-induced fluorescence detection instrument for cyanide detection

  Yasuhiro Morikawa; Keiji Nishiwaki; Shigeo Suzuki; Mitsuhiro Kinoshita; Isao Nakanishi

  Analytical Sciences Springer Science and Business Media LLC 38 (2) 437 - 442 0910-6340 2022/02 

  Cyanide is highly toxic to humans and the environment. It is very important to develop an on-site system for the quantitative analysis of cyanide with high sensitivity and reliability. In this study, we developed a cyanide detection system based on the reaction of vaporized cyanide on a glass-fiber filter soaked in a mixture of naphthalene-2,3-dicarboxaldehyde (NDA)-taurine-borate solution. Although the reaction product was stable for at least 3 days at room temperature, the reaction product on the strip was quickly quenched within a few minutes by direct irradiation with 405 nm light. To overcome this problem, we fabricated a simple device designed to detect the fluorescence intensity immediately after inserting a reaction strip into the device. The linearity of the calibration was obtained over a range of 1-100 µM of cyanide with good repeatability. The device is cost-effective (~ $300) and powered by batteries; therefore, it is suitable for the on-site determination of cyanide in crude samples.
• Fragment-based lead discovery to identify novel inhibitors that target the ATP binding site of pyruvate dehydrogenase kinases.

  Tatsuo Akaki; Yuki Bessho; Takashi Ito; Shingo Fujioka; Minoru Ubukata; Genki Mori; Kenji Yamanaka; Takuya Orita; Satoki Doi; Tomoko Iwanaga; Kazutaka Ikegashira; Yoshiji Hantani; Isao Nakanishi; Tsuyoshi Adachi

  Bioorganic & medicinal chemistry 44 116283 - 116283 2021/08 

  A fragment-based lead discovery approach was applied to Pyruvate Dehydrogenase Kinases (PDHKs) to discover inhibitors against the ATP binding site with novel chemotypes. X-ray fragment screening toward PDHK4 provided a fragment hit 1 with a characteristic interaction in a deep pocket of the ATP binding site. While known inhibitors utilize several water molecules in a deep pocket to form water-mediated hydrogen bond interactions, the fragment hit binds deeper in the pocket with a hydrophobic group. Displacement of a remaining water molecule in the pocket led to the identification of lead compound 7 with a notable improvement in inhibition potency. This lead compound possessed high ligand efficiency (LE) and showed decent selectivity profile. Two additional lead compounds 10 and 13 with new scaffolds with tricyclic and bicyclic cores were generated by merging structural information of another fragment hit 2. The characteristic interaction of these novel inhibitors in a deep pocket provides new structural insights about PDHKs ATP binding site and opens a novel direction for the development of PDHKs inhibitors.
• Elongation of the side chain by linear alkyl groups increases the potency of salacinol, a potent α-glucosidase inhibitor from the Ayurvedic traditional medicine "Salacia," against human intestinal maltase.

  Katsuki Takashima; Mika Sakano; Eri Kinouchi; Shinya Nakamura; Shinsuke Marumoto; Fumihiro Ishikawa; Kiyofumi Ninomiya; Isao Nakanishi; Toshio Morikawa; Genzoh Tanabe

  Bioorganic & medicinal chemistry letters 33 127751 - 127751 2021/02 

  Four chain-extended analogs (12a-12d) and two related de-O-sulfonated analogs (13a and 13c) by introducing alkyl groups (a: R = C3H7, b R = C6H13, c: R = C8H17, d: R = C10H21) to the side chains of salacinol (1), a natural α-glucosidase inhibitor from Ayurvedic traditional medicine "Salacia", were synthesized. The α-glucosidase inhibitory activities of all the synthesized analogs were evaluated in vitro. Against human intestinal maltase, the inhibitory activities of 12a and 13a with seven-carbon side chain were equal to that of 1. In contrast, analogs (12b-12d, and 13c) exhibited higher level of inhibitory activity against the same enzyme than 1 and had equal or higher potency than those of the clinically used anti-diabetics, voglibose, acarbose, and miglitol. Thus, elongation of the side chains of 1 was effective for specifically increasing the inhibitory activity against human intestinal maltase.
• Ligand compatibility of salacinol-type α-glucosidase inhibitors toward the GH31 family

  Fumihiro Ishikawa; Aiko Hirano; Yuuto Yoshimori; Kana Nishida; Shinya Nakamura; Katsuki Takashima; Shinsuke Marumoto; Kiyofumi Ninomiya; Isao Nakanishi; Weijia Xie; Toshio Morikawa; Osamu Muraoka; Genzoh Tanabe

  RSC Advances Royal Society of Chemistry ({RSC}) 11 (6) 3221 - 3225 2046-2069 2021 

  Salacinol-type α-glucosidase inhibitors are ligand-compatible with the GH 31 family. Salacinol and its 3′-O-benzylated analogs inhibit human lysosomal α-glucosidase at submicromolar levels.

• Activity, Binding, and Modeling Studies of a Reprogrammed Aryl Acid Adenylation Domain with an Enlarged Substrate Binding Pocket.

  Fumihiro Ishikawa; Hinano Kitayama; Shinya Nakamura; Katsuki Takashima; Isao Nakanishi; Genzoh Tanabe

  Chemical & pharmaceutical bulletin 69 (2) 222 - 225 2021 

  The gatekeeping adenylation (A) domain of the non-ribosomal peptide synthetase (NRPS) selectively incorporates specific proteinogenic/non-proteinogenic amino acid into a growing peptide chain. The EntE of the enterobactin NRPS is a discrete aryl acid A-domain with 2,3-dihydroxybenzoic acid (DHB) substrate specificity. Reprogrammed EntE N235G variant possesses an enlarged substrate recognition site, and is capable of accepting non-native aryl acids. Biochemical characterization of this unique substrate recognition site should provide a better understanding of activi-site microenvironments. Here, we synthesized a non-hydrolysable adenylate analogue with 2-aminobenzoic acid (2-ABA), 3-aminobenzoic acid (3-ABA), and 4-aminobenzoic acid (4-ABA) and used them to calculate the apparent inhibition constants (Kiapp.). Dose-response experiments using 3-ABA-sulfamoyladenosine (AMS) provided Kiapp. values of 596 nM for wild-type EntE and 2.4 nM for the N235G variants. These results suggest that 3-amino group of benzoic acid plays an important role in substrate recognition by the N235G variant. These findings would help designing aryl acid substrates with substituents at the 2- and 3-positions.
• Novel turn-on fluorescent sensor for cyanide ion based on the charge transfer transition of phenothiazine/indolium compounds

  Yasuhiro Morikawa; Miku Hirabara; Keiji Nishiwaki; Shigeo Suzuki; Isao Nakanishi

  Materials Advances Royal Society of Chemistry (RSC) 2 (18) 6104 - 6111 2021 

  A new fluorescent sensor combining phenothiazine and indolium, which reacts specifically with the cyanide ion with a large Stokes shift and a good fluorescence quantum yield, was prepared. When CN^-.
• A new chemosensor for cyanide in blood based on the Pd complex of 2-(5-bromo-2-pyridylazo)-5-[N-n-propyl-N-(3-sulfopropyl)amino]phenol.

  Yasuhiro Morikawa; Keiji Nishiwaki; Shigeo Suzuki; Naoyuki Yasaka; Yuto Okada; Isao Nakanishi

  The Analyst 145 (23) 7759 - 7764 2020/11 

  A new indirect chemosensor for the detection of cyanide in blood is developed. 2-(5-Bromo-2-pyridylazo)-5-[N-n-propyl-N-(3-sulfopropyl)amino]phenol, a yellow dye, forms a blue-coloured complex with palladium ions. The yellow colour of this complex is regained upon reaction with cyanide ions. The complex shows high selectivity for the detection of cyanide over 16 other anions. The system was applied to two different methods for the detection of cyanide in human whole blood. As a quantitative absorbance method, blood samples were mixed with acid, and the resulting vaporised hydrogen cyanide was absorbed in an alkaline solution containing the complex in a Conway cell. The resulting absorbance response of the solution at 450 nm is linear over the range 4-40 μM (R2 = 1.000), and the limit of detection is 0.6 μM. Furthermore, the complex-soaked paper is applicable as a test strip for cyanide detection. When a test strip is used with 0.5 mL of blood, the limit of detection is 15 μM. The detection limits of these two methods are below the toxic blood cyanide concentration (19 μM). Therefore, both methods allow the quantification and screening of cyanide in blood samples. Furthermore, the test strip is low cost and enables on-site analysis.
• Structural insights for producing CK2α1-specific inhibitors.

  Masato Tsuyuguchi; Tetsuko Nakaniwa; Akira Hirasawa; Isao Nakanishi; Takayoshi Kinoshita

  Bioorganic & medicinal chemistry letters 30 (2) 126837 - 126837 2020/01 [Refereed]
   

  Casein kinase 2 catalytic subunit (CK2α) is classified into two subtypes CK2α1 and CK2α2. CK2α1 is a drug discovery target, whereas CK2α2 is an off-target of CK2α1 inhibitors. High amino acid sequence homology between these subtypes hampers efforts to produce ATP competitive inhibitors that are highly selective to CK2α1. Hematein was identified previously as a non-ATP-competitive inhibitor for CK2α1, whereas this compound acts as an ATP competitive CK2α2 inhibitor. Crystal structures of CK2α1 and CK2α2 in complex with hematein revealed distinct binding features that provide structural insights for producing CK2α1-selective inhibitors.
• Precise Probing of Residue Roles by NRPS Code Swapping: Mutation, Enzymatic Characterization, Modeling, and Substrate Promiscuity of Aryl Acid Adenylation Domains.

  Fumihiro Ishikawa; Maya Nohara; Shinya Nakamura; Isao Nakanishi; Genzoh Tanabe

  Biochemistry 59 (4) 351 - 363 2020/01 [Refereed]
   

  Aryl acids are most commonly found in iron-scavenging siderophores but are not limited to them. The nonribosomal peptide synthetase (NRPS) codes of aryl acids remain poorly elucidated relative to those of amino acids. Here, we defined more precisely the role of active-site residues in aryl acid adenylation domains (A-domains) by gradually grafting the NRPS codes used for salicylic acid (Sal) into an archetypal aryl acid A-domain, EntE [specific for the substrate 2,3-dihydroxybenzoic acid (DHB)]. Enzyme kinetics and modeling studies of these EntE variants demonstrated that the NRPS code residues at positions 236, 240, and 339 collectively regulate the substrate specificity toward DHB and Sal. Furthermore, the EntE variants exhibited the ability to activate the non-native aryl acids 3-hydroxybenzoic acid, 3-aminobenzoic acid, 3-fluorobenzoic acid, and 3-chlorobenzoic acid. These studies enhance our knowledge of the NRPS codes of aryl acids and could be exploited to reprogram aryl acid A-domains for non-native aryl acids.
• A promiscuous kinase inhibitor delineates the conspicuous structural features of protein kinase CK2a1.

  Tsuyuguchi M; Nakaniwa T; Sawa M; Nakanishi I; Kinoshita T

  Acta crystallographica. Section F, Structural biology communications 75 (Pt 7) 515 - 519 2019/07 [Refereed]
   

  © 2019 International Union of Crystallography. Protein kinase CK2a1 is a serine/threonine kinase that plays a crucial role in the growth, proliferation and survival of cells and is a well known target for tumour and glomerulonephritis therapies. Here, the crystal structure of the kinase domain of CK2a1 complexed with 5-iodotubercidin (5IOD), an ATP-mimetic inhibitor, was determined at 1.78 Å resolution. The structure shows distinct structural features and, in combination with a comparison of the crystal structures of five off-target kinases complexed with 5IOD, provides valuable information for the development of highly selective inhibitors.
• An Engineered Aryl Acid Adenylation Domain with an Enlarged Substrate Binding Pocket.

  Ishikawa F; Miyanaga A; Kitayama H; Nakamura S; Nakanishi I; Kudo F; Eguchi T; Tanabe G

  Angewandte Chemie (International ed. in English) 58 (21) 6906 - 6910 1433-7851 2019/05 [Refereed]
   

  Adenylation (A) domains act as the gatekeepers of non-ribosomal peptide synthetases (NRPSs), ensuring the activation and thioesterification of the correct amino acid/aryl acid building blocks. Aryl acid building blocks are most commonly observed in iron-chelating siderophores, but are not limited to them. Very little is known about the reprogramming of aryl acid A-domains. We show that a single asparagine-to-glycine mutation in an aryl acid A-domain leads to an enzyme that tolerates a wide range of non-native aryl acids. The engineered catalyst is capable of activating non-native aryl acids functionalized with nitro, cyano, bromo, and iodo groups, even though no enzymatic activity of wild-type enzyme was observed toward these substrates. Co-crystal structures with non-hydrolysable aryl-AMP analogues revealed the origins of this expansion of substrate promiscuity, highlighting an enlargement of the substrate binding pocket of the enzyme. Our findings may be exploited to produce diversified aryl acid containing natural products and serve as a template for further directed evolution in combinatorial biosynthesis.
• Structure-Activity Relationships and Docking Studies of Hydroxychavicol and Its Analogs as Xanthine Oxidase Inhibitors.

  Nishiwaki K; Ohigashi K; Deguchi T; Murata K; Nakamura S; Matsuda H; Nakanishi I

  Chemical & Pharmaceutical Bulletin 66 (7) 741 - 747 0009-2363 2018/07 [Refereed]
   

  Hydroxychavicol (HC), which is obtained from the leaves of Piper betle LINN. (Piperaceae), inhibits xanthine oxidase (XO) with an IC50 value of 16.7 µM, making it more potent than the clinically used allopurinol (IC50=30.7 µM). Herein, a structure-activity relationship analysis of the polar part analogs of HC was conducted and an inhibitor was discovered with a potency 13 times that of HC. Kinetic studies have revealed that HC and its active analog inhibit XO in an uncompetitive manner. The binding structure prediction of these inhibitor molecules to the XO complex with xanthine suggested that both compounds (HC and its analog) could simultaneously form hydrogen bonds with xanthine and XO.
• Synthesis of jaspine B regioisomers through palladium-catalyzed stereoselective tetrahydrofuran formation: Insight into the ligand recognition of sphingosine kinases

  Miyagawa Takashi; Inuki Shinsuke; Honda Maho; Nakamura Shinya; Nakanishi Isao; Fujii Nobutaka; Oishi Shinya; Ohno Hiroaki

  TETRAHEDRON 74 (15) 1802 - 1809 0040-4020 2018/04 [Refereed]
  
• Improvement of pseudo- molecule generation on solvent dipole ordering virtual screening (SDO-VS)

  Shinya Nakamura; Hayao Kitayoshi; Isao Nakanishi

  J. Comp. Aided Chem. Division of Chemical Information and Computer Sciences The Chemical Society of Japan 18 149 - 158 2017/10 [Refereed]
   

  Solvent dipole ordering virtual screening (SDO-VS) is a virtual screening method that focuses on the shape of the SDO region at the binding site of the protein. In SDO-VS, pseudo molecules (PMs) are generated to reproduce the shape of the SDO region. Compounds that have shapes (or volumes) similar to those of the PMs are then screened from a 3D structure database. The original implementation of SDO-VS involved PMs with only sp3-hybridized carbon atoms. However, utilization of sp2- and sp-hybridized atoms and/or small molecular fragments, in addition to sp3-hybridized atoms, is expected to provide more efficient screening. To this end, this study investigated the effect of sp3-, sp2-, and sp-hybridized atoms and phenyl rings as fragments for PM generation in the SDO-VS method. The screening efficiencies were compared with the original method for several drug target proteins. Overall, this new method improved screening efficiencies, as measured by the area under the curve of the corresponding receiver operating characteristic plots.
• An interaction-based approach for affinity prediction between antigen peptide and human leukocyte antigen using COMBINE analysis

  Shinya Nakamura; Rie Ohmura; Isao Nakanishi

  Chem-Bio Informatics Journal Chem-Bio Informatics Society 17 93 - 102 1347-0442 2017/09 [Refereed]
   

  In peptide vaccine therapy, a peptide with high affinity for human leukocyte antigen (HLA), is important to stimulate the immune system to kill cancer cells. Several methods to predict HLA–peptide binding have been reported, but most of them rely on informatics to analyze the amino acid sequence of the peptide. Although intermolecular-interaction-based analysis is expected to improve prediction accuracy, such a method generally involves a high computational cost. Therefore, comparative binding energy (COMBINE) analysis, a 3D-quantitative structure–activity relationship method, combined with a rapidly implemented protein modeling method, was applied to solve this problem. The new method enabled quick evaluation of peptide affinity predictions with accuracy beyond a statistical method. In addition, several amino acid residues of HLA, which are known to be important for peptide binding, could be identified.
• Computational study on the comparative differences in the activity of inhibitors of human versus rat alpha-glucosidase.

  Shinya Nakamura; Kazuko Shimada; Genzoh Tanabe; Osamu Muraoka; Isao Nakanishi

  Open J. Med. Chem. 7 19 - 28 2017/06 [Refereed]
  
• Identification of selective inhibitors of sphingosine kinases 1 and 2 through a structure-activity relationship study of 4-epi-jaspine B

  Hiroaki Ohno; Maho Honda; Naoka Hamada; Jun Miyagaki; Akira Iwata; Kazuhiro Otsuki; Toru Maruyama; Shinya Nakamura; Isao Nakanishi; Shinsuke Inuki; Nobutaka Fujii; Shinya Oishi

  BIOORGANIC & MEDICINAL CHEMISTRY PERGAMON-ELSEVIER SCIENCE LTD 25 (12) 3046 - 3052 0968-0896 2017/06 [Refereed]
   

  We recently reported that 4-epi-jaspine B exhibits potent inhibitory activity towards sphingosine kinases (SphKs). In this study, we investigated the effects of modifying the 2-alkyl group, as well as the functional groups on the THE ring of 4-epi-jaspine B using a diversity-oriented synthesis approach based on a late stage cross metathesis reaction. The introduction of a p-phenylene tether to the alkyl group was favored in most cases, whereas the replacement of a carbon atom with an oxygen atom led to a decrease in the inhibitory activity. Furthermore, the introduction of a bulky alkyl group at the terminus led to a slight increase in the inhibitory activity of this series towards SphKs compared with 4-epi-jaspine B (the Q values of compound 13 for SphK1 and SphK2 were 0.2 and 0.4, respectively). Based on this study, we identified two isoform selective inhibitors, including the m-phenylene derivative 4 [IC50 (SphK1) >= 30 mu M; IC50 (SphK2) = 2.2 mu M] and the methyl ether derivative 22 [IC50 (SphK1) = 4.0 mu M; IC50 (SphK2) >= 30 mu m]. (C) 2017 Elsevier Ltd. All rights reserved.
• Synthesis and Functional Characterization of Novel Sialyl LewisX Mimic-Decorated Liposomes for E-selectin-Mediated Targeting to Inflamed Endothelial Cells

  Chanikarn Chantarasrivong; Akiharu Ueki; Ryutaro Ohyama; Johan Unga; Shinya Nakamura; Isao Nakanishi; Yuriko Higuchi; Shigeru Kawakami; Hiromune Ando; Akihiro Imamura; Hideharu Ishida; Fumiyoshi Yamashita; Makoto Kiso; Mitsuru Hashida

  MOLECULAR PHARMACEUTICS AMER CHEMICAL SOC 14 (5) 1528 - 1537 1543-8384 2017/05 [Refereed]
   

  Sialyl LewisX (sLeX) is a natural ligand of E-selectin that is overexpressed by inflamed and tumor endothelium. Although sLeX is a potential ligand for drug targeting, synthesis of the tetrasaccharide is complicated with many reaction steps. In this study, structurally simplified novel sLeX analogues were designed and linked with 1,2-distearoylsn-glycero-3-phosphoethanolamine-polyethylene glycol-2000 (DSPE-PEG) for E-selectin-mediated liposomal delivery. The sLeX structural simplification strategies include (1) replacement of the Gal-G1cNAc disaccharide unit with lactose to reduce many initial steps and (2) substitution of neuraminic acid with a negatively charged group, i.e., 3'-sulfo, 3'-carboxymethyl (3'-CM), or 3'-(1-carboxy)ethyl (3'-CE). While all the liposomes developed were similar in particle size and charge, the 3'-CE sLeX mimic liposome demonstrated the highest uptake in inflammatory cytokine-treated human umbilical vein endothelial cells (HUVECs), being even more potent than native sLeX-decorated liposomes. Inhibition studies using antiselectin antibodies revealed that their uptake was mediated primarily by overexpressed E-sdectin on inflamed HUVECs. Molecular dynamics simulations were performed to gain mechanistic insight into the E-selectin binding differences among native and mimic sLeX. The terminally branched methyl group of the 3'-CE sLeX mimic oriented and faced the bulk hydrophilic solution during. E-selectin binding. Since this state is entropically unfavorable, the 3'-CE sLeX mimic molecule might be pushed toward the binding, pocket of E-selectin by a hydrophobic effect, leading to a higher probability of hydrogen-bond' formation than native sLeX and the 3'-CM sLeX mimic. This corresponded with the fact that the 3'-CE sLeX mimic liposome exhibited much greater uptake than the 3'-CM sLeX mimic liposome.
• Hydrophobic substituents increase the potency of salacinol, a potent alpha-glucosidase inhibitor from Ayurvedic traditional medicine 'Salacia'

  Genzoh Tanabe; Weijia Xie; Gorre Balakishan; Mumen F. A. Amer; Nozomi Tsutsui; Haruka Takemura; Shinya Nakamura; Junji Akaki; Kiyofumi Ninomiya; Toshio Morikawa; Isao Nakanishi; Osamu Muraoka

  BIOORGANIC & MEDICINAL CHEMISTRY PERGAMON-ELSEVIER SCIENCE LTD 24 (16) 3705 - 3715 0968-0896 2016/08 [Refereed]
   

  Using an in silico method, seven analogs bearing hydrophobic substituents (8a: Me, 8b: Et, 8c: n-Pent, 8d: n-Hept, 8e: n-Tridec, 8f: isoBu and 8g: neoPent) at the 3'-O-position in salacinol (1), a highly potent natural alpha-glucosidase inhibitor from Ayurvedic traditional medicine 'Salacia', were designed and synthesized. In order to verify the computational SAR assessments, their alpha-glucosidase inhibitory activities were evaluated in vitro. All analogs (8a-8g) exhibited an equal or considerably higher level of inhibitory activity against rat small intestinal alpha-glucosidases compared with the original sulfonate (1), and were as potent as or higher in potency than the clinically used anti-diabetics, voglibose, acarbose or miglitol. Their activities against human maltase exhibited good relationships to the results obtained with enzymes of rat origin. Among the designed compounds, the one with a 3'-O-neopentyl moiety (8g) was most potent, with an approximately ten fold increase in activity against human maltase compared to 1. (C) 2016 Elsevier Ltd. All rights reserved.
• Structure-activity relationship study of 4-(thiazol-5-yl)benzoic acid derivatives as potent protein kinase CK2 inhibitors

  Hiroaki Ohno; Daiki Minamiguchi; Shinya Nakamura; Keito Shu; Shiho Okazaki; Maho Honda; Ryosuke Misu; Hirotomo Moriwaki; Shinsuke Nakanishi; Shinya Oishi; Takayoshi Kinoshita; Isao Nakanishi; Nobutaka Fujii

  BIOORGANIC & MEDICINAL CHEMISTRY PERGAMON-ELSEVIER SCIENCE LTD 24 (5) 1136 - 1141 0968-0896 2016/03 [Refereed]
   

  Two classes of modified analogs of 4-(thiazol-5-yl)benzoic acid-type CK2 inhibitors were designed. The azabenzene analogs, pyridine-and pyridazine-carboxylic acid derivatives, showed potent protein kinase CK2 inhibitory activities [IC50 (CK2 alpha) = 0.014-0.017 mu M; IC50 (CK2 alpha') = 0.0046-0.010 mu M]. Introduction of a 2-halo- or 2-methoxy-benzyloxy group at the 3-position of the benzoic acid moiety maintained the potent CK2 inhibitory activities [IC50 (CK2 alpha) = 0.014-0.016 mu M; IC50 (CK2 alpha') = 0.0088-0.014 mu M] and led to antiproliferative activities [CC50 (A549) = 1.5-3.3 mu M] three to six times higher than those of the parent compound. (C) 2016 Elsevier Ltd. All rights reserved.
• Identification of protein kinase CK2 inhibitors using solvent dipole ordering virtual screening

  Isao Nakanishi; Katsumi Murata; Naoya Nagata; Masakuni Kurono; Takayoshi Kinoshita; Misato Yasue; Takako Miyazaki; Yoshinori Takei; Shinya Nakamura; Atsushi Sakurai; Nobuko Iwamoto; Keiji Nishiwaki; Tetsuko Nakaniwa; Yusuke Sekiguchi; Akira Hirasawa; Gozoh Tsujimoto; Kazuo Kitaura

  EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER 96 396 - 404 0223-5234 2015/05 [Refereed]
   

  Novel protein kinase CK2 inhibitors were identified using the solvent dipole ordering virtual screening method. A total of 26 compounds categorized in 15 distinct scaffold classes inhibited greater than 50% of enzyme activity at 50 mu M, and eight exhibited IC50 values less than 10 mu M. Most of the identified compounds are lead-like and dissimilar to known inhibitors. The crystal structures of two of the CK2 complexes revealed the high accuracy of the predicted binding modes. (C) 2015 Elsevier Masson SAS. All rights reserved.
• The Use of Many-Body Expansions and Geometry Optimizations in Fragment-Based Methods

  Dmitri G. Fedorov; Naoya Asada; Isao Nakanishi; Kazuo Kitaura

  ACCOUNTS OF CHEMICAL RESEARCH AMER CHEMICAL SOC 47 (9) 2846 - 2856 0001-4842 2014/09 [Refereed]
   

  CONSPECTUS: Chemists routinely work with complex molecular systems: solutions, biochemical molecules, and amorphous and composite materials provide some typical examples. The questions one often asks are what are the driving forces for a chemical phenomenon? How reasonable are our views of chemical systems in terms of subunits, such as functional groups and individual molecules? How can one quantify the difference in physicochemical properties of functional units found in a different chemical environment? Are various effects on functional units in molecular systems additive? Can they be represented by pairwise potentials? Are there effects that cannot be represented in a simple picture of pairwise interactions? How can we obtain quantitative values for these effects? Many of these questions can be formulated in the language of many-body effects. They quantify the properties of subunits (fragments), referred to as one-body properties, pairwise interactions (two-body properties), couplings of two-body interactions described by three-body properties, and so on. By introducing the notion of fragments in the framework of quantum chemistry, one obtains two immense benefits: (a) chemists can finally relate to quantum chemistry, which now speaks their language, by discussing chemically interesting subunits and their interactions and (b) calculations become much faster due to a reduced computational scaling. For instance, the somewhat academic sounding question of the importance of three-body effects in water clusters is actually another way of asking how two hydrogen bonds affect each other, when they involve three water molecules. One aspect of this is the many-body charge transfer (CT), because the charge transfers in the two hydrogen bonds are coupled to each other (not independent). In this work, we provide a generalized view on the use of many-body expansions in fragment-based methods, focusing on the general aspects of the property expansion and a contraction of a many-body expansion in a formally two-body series, as exemplified in the development of the fragment molecular orbital (FMO) method. Fragment-based methods have been very successful in delivering the properties of fragments, as well as the fragment interactions, providing insights into complex chemical processes in large molecular systems. We briefly review geometry optimizations performed with fragment-based methods and present an efficient geometry optimization method based on the combination of FMO with molecular mechanics (MM), applied to the complex of a subunit of protein kinase 2 (CK2) with a ligand. FMO results are discussed in comparison with experimental and MM-optimized structures.
• Optimization of diaryl amine derivatives as kinesin spindle protein inhibitors

  Tomoki Takeuchi; Shinya Oishi; Masato Kaneda; Ryosuke Misu; Hiroaki Ohno; Jun-ichi Sawada; Akira Asai; Shinya Nakamura; Isao Nakanishi; Nobutaka Fujii

  BIOORGANIC & MEDICINAL CHEMISTRY PERGAMON-ELSEVIER SCIENCE LTD 22 (12) 3171 - 3179 0968-0896 2014/06 [Refereed]
   

  Structure-activity relationship studies of diaryl amine-type KSP inhibitors were carried out. Diaryl amine derivatives with a pyridine ring or urea group were less active when compared with the parent carboline and carbazole derivatives. Optimization studies of a lactam-fused diphenylamine-type KSP inhibitor revealed that the aniline NH group and 3-CF3 phenyl group were indispensable for potent KSP inhibition. Modification with a seven-membered lactam-fused phenyl group and a 4-(trifluoromethyl)pyridin-2-yl group improved aqueous solubility while maintaining potent KSP inhibitory activity. From these studies, we identified novel diaryl amine-type KSP inhibitors with a favorable balance of potency and solubility. (C) 2014 Elsevier Ltd. All rights reserved.
• Kinesin Spindle Protein Inhibitors with Diaryl Amine Scaffolds: Crystal Packing Analysis for Improved Aqueous Solubility

  Tomoki Takeuchi; Shinya Oishi; Masato Kaneda; Hiroaki Ohno; Shinya Nakamura; Isao Nakanishi; Masayoshi Yamane; Jun-ichi Sawada; Akira Asai; Nobutaka Fujii

  ACS MEDICINAL CHEMISTRY LETTERS AMER CHEMICAL SOC 5 (5) 566 - 571 1948-5875 2014/05 [Refereed]
   

  Diaryl amine derivatives have been designed and synthesized as novel kinesin spindle protein (KSP) inhibitors based on planar carbazole-type KSP inhibitors with poor aqueous solubility. The new generation of inhibitors was found to show comparable inhibitory activity and high selectivity for KSP, and this was accompanied with improved solubility. Kinetic analysis and molecular modeling studies suggested that these inhibitors work in an ATP-competitive manner via binding to the secondary allosteric site formed by alpha 4 and alpha 6 helices of KSP. Comparative structural investigations on a series of compounds revealed that the higher solubility of diaryl amine-type inhibitors was attributed to fewer van der Waals interactions in the crystal packing and the hydrogen-bond acceptor nitrogen of the aniline moiety for favorable solvation.
• A 7-dimethylallyl tryptophan synthase from a fungal Neosartorya sp.: Biochemical characterization and structural insight into the regioselective prenylation

  Kengo Miyamoto; Fumihiro Ishikawa; Shinya Nakamura; Yutaka Hayashi; Isao Nakanishi; Hideaki Kakeya

  BIOORGANIC & MEDICINAL CHEMISTRY PERGAMON-ELSEVIER SCIENCE LTD 22 (8) 2517 - 2528 0968-0896 2014/04 [Refereed]
   

  A putative 7-dimethylallyl tryptophan synthase (DMATS) gene from a fungal Neosartorya sp. was cloned and overexpressed as a soluble His(6)-fusion protein in Escherichia coli. The enzyme was found to catalyze the prenylation of L-tryptophan at the C7 position of the indole moiety in the presence of dimethylallyl diphosphate; thus, it functions as a 7-DMATS. In this study, we describe the biochemical characterization of 7-DMATS from Neosartorya sp., referred to as 7-DMATS(Neo), and the structural basis of the regioselective prenylation of L-tryptophan at the C7 position by comparison of the three-dimensional structural models of 7-DMATS(Neo) with FgaPT2 (4-DMATS) from Aspergillus fumigatus. (C) 2014 Elsevier Ltd. All rights reserved.
• Crystal structure of human CK2 alpha at 1.06 angstrom resolution

  Takayoshi Kinoshita; Tetsuko Nakaniwa; Yusuke Sekiguchi; Yuri Sogabe; Atsushi Sakurai; Shinya Nakamura; Isao Nakanishi

  JOURNAL OF SYNCHROTRON RADIATION WILEY-BLACKWELL 20 (Pt 6) 974 - 979 0909-0495 2013/11 [Refereed]
   

  The Ser/Thr kinase CK2 consists of two catalytic subunits (CK2 alpha) and a dimer of the regulatory subunits (CK2 beta), and is a ubiquitous enzyme that regulates growth, proliferation and the survival of cells. CK2 is a remarkable drug target for potentially treating a wide variety of tumours and glomerulonephritis. The purified CK2 alpha protein was crystallized using ethylene glycol as a precipitant. The crystal structure of CK2 alpha with 21 loci of alternative conformations, including a niacin, 19 ethylene glycols and 346 waters, was determined at 1.06 angstrom resolution to an R-work of 14.0% (R-free = 16.5%). The alternative ensemble in the internal hydrophobic core underpins the plasticity of the alpha D-helix responsible for the regulation of ATP/GTP binding. The clear density map indicates that a niacin molecule, contained in the Escherichia coli culture medium, binds to the ATP binding site. An ethylene glycol molecule binds in the hydrophobic pocket lateral to the alpha D-helix forming the rim of the active site. The other ethylene glycol molecules occupy physiologically significant sites, including the CK2 beta binding interface and substrate binding site, as well as the gap in the crystal packing. Together with water molecules in the active site, these structural insights should facilitate drug discovery.
• Diversity-oriented synthesis of pyrazolo[4,3-b]indoles by gold-catalysed three-component annulation: application to the development of a new class of CK2 inhibitors

  Zengye Hou; Shinya Oishi; Yamato Suzuki; Tatsuhide Kure; Isao Nakanishi; Akira Hirasawa; Gozoh Tsujimoto; Hiroaki Ohno; Nobutaka Fujii

  ORGANIC & BIOMOLECULAR CHEMISTRY ROYAL SOC CHEMISTRY 11 (20) 3288 - 3296 1477-0520 2013 [Refereed]
   

  Pyrazolo[4,3-b]indole derivatives have been designed as novel CK2 inhibitor compounds based on the binding mode analysis of a previously reported phenylpyrazole-type CK2 inhibitor. A series of pyrazolo[ 4,3-b]indoles and related dihydropyrazolo[4,3-b]indoles were efficiently prepared from simple starting materials using a gold-catalysed three-component annulation reaction as a key step. Several of the newly synthesized compounds displayed high levels of inhibitory activity, indicating that the pyrazolo[4,3-b]indole core represents a promising scaffold for the development of potent CK2 inhibitors.
• Role of the side chain stereochemistry in the alpha-glucosidase inhibitory activity of kotalanol, a potent natural alpha-glucosidase inhibitor. Part 2

  Genzoh Tanabe; Kanjyun Matsuoka; Masahiro Yoshinaga; Weijia Xie; Nozomi Tsutsui; Mumen F. A. Amer; Shinya Nakamura; Isao Nakanishi; Xiaoming Wu; Masayuki Yoshikawa; Osamu Muraoka

  BIOORGANIC & MEDICINAL CHEMISTRY PERGAMON-ELSEVIER SCIENCE LTD 20 (21) 6321 - 6334 0968-0896 2012/11 [Refereed]
   

  To examine the role of the side chain of kotalanol (2), a potent natural alpha-glucosidase inhibitor isolated from Salacia reticulata, on inhibitory activity, four diastereomers (11a-11d) with reversed configuration (S) at the C-4' position in the side chain were synthesized and evaluated. Two of the four (11b and 11d) significantly lost their inhibitory activity against both maltase and sucrase, while the other two (11a and 11c) sustained the inhibitory activity to a considerable extent, showing distinct activity in response to the change of stereochemistry of the hydroxyls at the 5' and 6' positions. Different activities were rationalized with reference to in silico docking studies on these inhibitors with hNtMGAM. Against isomaltase, all four analogs showed potent inhibitory activity as well as 2, and 11b and 11d exhibited enzyme selectivity. (C) 2012 Elsevier Ltd. All rights reserved.
• Homology Modeling of Human alpha-glucosidase catalytic domains and SAR study of salacinol derivatives

  Nakamura S; Takahira K; Tanabe G; Muraoka O; Nakanishi I

  Open Journal of Medicinal Chemistry 2 (3) 50 - 60 2012/09
• An Efficient Method to Evaluate Intermolecular Interaction Energies in Large Systems Using Overlapping Multicenter ONIOM and the Fragment Molecular Orbital Method

  Naoya Asada; Dmitri G. Fedorov; Kazuo Kitaura; Isao Nakanishi; Kenneth M. Merz

  JOURNAL OF PHYSICAL CHEMISTRY LETTERS AMER CHEMICAL SOC 3 (18) 2604 - 2610 1948-7185 2012/09 [Refereed]
   

  We propose an approach based on the overlapping multicenter ONIOM to evaluate intermolecular interaction energies in large systems and demonstrate its accuracy on several representative systems in the complete basis set limit at the MP2 and CCSD(T) level of theory. In the application to the intermolecular interaction energy between insulin dimer and 4'-hydroxyacetanilide at the MP2/CBS level, we use the fragment molecular orbital method for the calculation of the entire complex assigned to the lowest layer in three-layer ONIOM. The developed method is shown to be efficient and accurate in the evaluation of the protein-ligand interaction energies.
• Subtle Structural Changes in Tetrahydroquinolines, A New Class of Nonsteroidal Selective Androgen Receptor Modulators, Induce Different Functions

  Naoya Nagata; Kentaro Kawai; Isao Nakanishi

  JOURNAL OF CHEMICAL INFORMATION AND MODELING AMER CHEMICAL SOC 52 (8) 2257 - 2264 1549-9596 2012/08 [Refereed]
   

  Tetrahydroquinolines (THQs), a new class of nonsteroidal selective androgen receptor (AR) modulators, have two indispensable functional groups, that is, a hydroxyl group for AR binding and a nitro group for agonistic. activity. Interestingly, switching the nitro to a cyano group, the compound :acts as an antagonist To understand this phenomenon, molecular dynamics simulations were applied for dihydrotestosterone (DHT) and representative THQs complexes with AR. Upon ligand binding, the hydroxyl group formed a tight hydrogen bond (H-bond) with Asn705 on Helix 3, (H3). The immobilization of Asn705 on H3 is helpful in the formation Of tight H-bonds with Asp890 on loop 11-12, and this immobilization consequently leads to a stabilization of H12. The difference in the DHT carbonyl isosteres affected the presence or absence of the H-bonds between the hydroxyl group of THQ and Thr877 and the distortion of H12, which is caused by the methyl group of THQ Thus, the binding, agonist, and antagonist functions were controlled by subtle structural changes in THQ,
• Structure-Based Design Of Novel Potent Protein Kinase CK2 (CK2) Inhibitors with Phenyl-azole Scaffolds

  Zengye Hou; Isao Nakanishi; Takayoshi Kinoshita; Yoshinori Takei; Misato Yasue; Ryosuke Misu; Yamato Suzuki; Shinya Nakamura; Tatsuhide Kure; Hiroald Ohno; Katsumi Murata; Kazuo Kitaura; Akira Hirasawa; Gozoh Tsujimoto; Shinya Oishi; Nobutaka Fujii

  JOURNAL OF MEDICINAL CHEMISTRY AMER CHEMICAL SOC 55 (6) 2899 - 2903 0022-2623 2012/03 [Refereed]
   

  Protein kinase CK2 (CK2) is a ubiquitous serine/threonine protein kinase for hundreds of endogenous substrates. CK2 has been considered to be involved in many diseases, including cancers. Herein we report the discovery of a novel ATP-competitive CK2 inhibitor. Virtual screening of a compound library led to the identification of a hit 2-phenyl-1,3,4-thiadiazole compound. Subsequent structural optimization resulted in the identification of a promising 4-(thiazol-5-yl)benzoic acid derivative.
• P-7 In Silico Design, Synthesis and Evaluation of Salacinol Analogs, a New Class of α-Glucosidase Inhibitors with Sulfonium Salts Structure(Poster Presentation)

  Tanabe Genzoh; Yoshikawa Masayuki; Muraoka Osamu; Nakamura Shinya; Yoshinaga Masahiro; Tsutsui Nozomi; Balakishan Gorre; Akaki Junji; Morikawa Toshio; Ninomiya Kiyofumi; Nakanishi Isao

  Symposium on the Chemistry of Natural Products, symposium papers 天然有機化合物討論会実行委員会 54 (0) 285 - 290 2012 

  To develop more potent α-glucosidase inhibitors whose seed-compound is salacinol (1), a potent natural α-glucosidase inhibitor isolated from Salacia reticulata of Ayurvedic traditional medicine, a series of 3'-O-benzylated analogs of 1 were designed with the aid of in silico method. Intensive docking studies proposed several promising compounds. To verify the computational SAR assessments, designed derivatives were synthesized and evaluated in vitro. Their α-glucosidase inhibitory activities against rat intestinal α-glucosidases were so potent as were expected by the docking studies, and all the compounds showed superior inhibitory activities to the original sulfonium sulfate (1). Among the sulfonium salts designed, one with 3'-O-(ortho-nitrobenzyl) moiety (8k) was found to be the most potent, and ca. forty times as potent as 1, the compound being the strongest inhibitor among the sulfonium type inhibitors synthesized so far. [chemical formula]
• Design and synthesis of a novel class of CK2 inhibitors: application of copper- and gold-catalysed cascade reactions for fused nitrogen heterocycles

  Yamato Suzuki; Shinya Oishi; Yoshinori Takei; Misato Yasue; Ryosuke Misu; Saori Naoe; Zengye Hou; Tatsuhide Kure; Isao Nakanishi; Hiroaki Ohno; Akira Hirasawa; Gozoh Tsujimoto; Nobutaka Fujii

  ORGANIC & BIOMOLECULAR CHEMISTRY ROYAL SOC CHEMISTRY 10 (25) 4907 - 4915 1477-0520 2012 [Refereed]
   

  Two classes of fused nitrogen heterocycles were designed as CK2 inhibitor candidates on the basis of previous structure-activity relationship (SAR) studies. Various dipyrrolo[3,2-b:2',3'-e]pyridine and benzo[g] indazole derivatives were prepared using transition-metal-catalysed cascade and/or multicomponent reactions. Biological evaluation of these candidates revealed that benzo[g] indazole is a promising scaffold for potent CK2 inhibitors. The inhibitory activities on cell proliferation of these potent CK2 inhibitors are also presented.
• In silico design, synthesis and evaluation of 3 '-O-benzylated analogs of salacinol, a potent alpha-glucosidase inhibitor isolated from an Ayurvedic traditional medicine "Salacia"

  Genzoh Tanabe; Shinya Nakamura; Nozomi Tsutsui; Gorre Balakishan; Weijia Xie; Satoshi Tsuchiya; Junji Akaki; Toshio Morikawa; Kiyofumi Ninomiya; Isao Nakanishi; Masayuki Yoshikawa; Osamu Muraoka

  CHEMICAL COMMUNICATIONS ROYAL SOC CHEMISTRY 48 (69) 8646 - 8648 1359-7345 2012 [Refereed]
   

  With the aid of an in silico method, alpha-glucosidase inhibitors with far more potent activities than salacinol (1), a potent natural alpha-glucosidase inhibitor isolated from an Ayurvedic traditional medicine Salacia reticulata, have been developed.
• A detailed thermodynamic profile of cyclopentyl and isopropyl derivatives binding to CK2 kinase

  Takayoshi Kinoshita; Yusuke Sekiguchi; Harumi Fukada; Tetsuko Nakaniwa; Toshiji Tada; Shinya Nakamura; Kazuo Kitaura; Hiroaki Ohno; Yamato Suzuki; Akira Hirasawa; Isao Nakanishi; Gozoh Tsujimoto

  MOLECULAR AND CELLULAR BIOCHEMISTRY SPRINGER 356 (1-2) 97 - 105 0300-8177 2011/10 [Refereed]
   

  The detailed understanding of the molecular features of a ligand binding to a target protein, facilitates the successful design of potent and selective inhibitors. We present a case study of ATP-competitive kinase inhibitors that include a pyradine moiety. These compounds have similar chemical structure, except for distinct terminal hydrophobic cyclopentyl or isopropyl groups, and block kinase activity of casein kinase 2 subunit alpha (CK2 alpha), which is a target for several diseases, such as cancer and glomerulonephritis. Although these compounds display similar inhibitory potency against CK2 alpha, the crystal structures reveal that the cyclopentyl derivative gains more favorable interactions compared with the isopropyl derivative, because of the additional ethylene moiety. The structural observations and biological data are consistent with the thermodynamic profiles of these inhibitors in binding to CK2 alpha, revealing that the enthalpic advantage of the cyclopentyl derivative is accompanied with a lower entropic loss. Computational analyses indicated that the relative enthalpic gain of the cyclopentyl derivative arises from an enhancement of a wide range of van der Waals interactions from the whole complex. Conversely, the relative entropy loss of the cyclopentyl derivative arises from a decrease in the molecular fluctuation and higher conformational restriction in the active site of CK2 alpha. These structural insights, in combination with thermodynamic and computational observations, should be helpful in developing potent and selective CK2 alpha inhibitors.
• Role of the side chain stereochemistry in the α-glucosidase inhibitory activity of kotalanol, a potent natural α-glucosidase inhibitor

  G. Tanabe; K. Matsuoka; M. Yoshinaga; W. Xie; N. Tsutsui; M. F. A. Amer; S. Nakamura; I. Nakanishi; X. Wu; M. Yoshikawa; O. Muraoka

  Bioorg. Med. Chem. 19 2252 - 2262 2011/04 [Refereed]
  
• Binding mode prediction of a CK2 inhibitor, Hematein by the MM/PBSA method

  Nagamatsu Kazuhiko; Nakamura Shinya; Kinoshita Takayoshi; Hirasawa Akira; Tsujimoto Gozoh; Nakanishi Isao

  Symposium on Chemical Information and Computer Sciences The Chemical Society of Japan 2011 P2 - P2 2011 

  Casein kinase II (CK2), a serine-threonine protein kinase, is distributed ubiquitously in human body. It exists as a tetramer composed of two catalytic subunits (α and α') and two control subunits (β). Amino acid sequence homology between the catalytic subunit α and α' is very high, 83%. Inhibitors of this enzyme have been explored for cancer, virus infection and glomerulonephritis therapies, and several highly potent compounds have been reported as ATP competitive inhibitors. On the other hand, hematein, a natural compound isolated from Caesalpinia sappan, inhibits CK2α in an ATP uncompetitive manner, whereas it inhibits CK2α' in a competitive manner. We have investigated the binding mode of hematein to both isozymes using docking studies followed by the binding energy analysis with the MM/PBSA method and the simulated annealing simulation. The results suggested that hematein could bind to the ATP binding site of the both isozymes. In addition, it might bind to the allosteric site and the substrate binding site of CK2α.
• Estimation of the binding free energy differences between protein ligands by the FEP/TI method

  Nakao Yoshihito; Nakamura Shinya; Nakanishi Isao

  Symposium on Chemical Information and Computer Sciences The Chemical Society of Japan 2011 P20 - P20 2011 

  Binding free energy ΔGbind of a ligand to the target protein is a physicochemical quantity which closely relates to a drug activity, and prediction of ΔGbind with accuracy leads to an efficient drug design. As a method to calculate ΔΔGbind, difference of ΔGbind between two ligands, FEP (free energy perturbation) and TI (thermodynamic integration) methods are well known. Theoretically, application of these methods are limited to the system where an energy difference is small, ~2 kcal/mol. Recently, Jorgensen et al. have applied these methods to a lead optimization study of HIV reverse transcriptase inhibitors, and succeeded in obtaining a qualitative relationship between the predicted and experimental values. However, it is desirable to establish an appropriate calculation procedure of these methods which reproduces experimental ΔΔGbind quantitatively. In this study, we applied the FEP/TI methods to the FXa (activated blood coagulation factor X) inhibitors, where one hydrogen atom on an inhibitor molecule was replaced with a chlorine atom. Several calculation procedures have been tested.
• SDOVS: A Solvent Dipole Ordering-Based Method for Virtual Screening

  Katsumi Murata; Naoya Nagata; Isao Nakanishi; Kazuo Kitaura

  JOURNAL OF COMPUTATIONAL CHEMISTRY WILEY-BLACKWELL 31 (15) 2714 - 2722 0192-8651 2010/11 

  We previously reported that solvent dipole ordering (SDO) at the ligand binding site of a protein indicates an outline of the preferred shape and binding pose of the ligands. We suggested that SDO-mimetic pseudo-molecules that mimic the 3D shape of the SDO region could be used as molecular queries with a shape similarity matching method in virtual screening. In this work, a virtual screening method based on SDO, named SDOVS, was proposed. This method was applied to virtual screening of ligands for four typical drug target proteins and the performance compared with that of FRED (well-known rigid docking method); the efficiency of SDOVS was demonstrated to be better than FRED. (C) 2010 Wiley Periodicals, Inc. J Comput Chem 31: 2714-2722, 2010
• Docking and SAR studies of salacinol derivatives as alpha-glucosidase inhibitors

  Shinya Nakamura; Kazunori Takahira; Genzoh Tanabe; Toshio Morikawa; Mika Sakano; Kiyofumi Ninomiya; Masayuki Yoshikawa; Osamu Muraoka; Isao Nakanishi

  BIOORGANIC & MEDICINAL CHEMISTRY LETTERS PERGAMON-ELSEVIER SCIENCE LTD 20 (15) 4420 - 4423 0960-894X 2010/08 

  Salacinol is a potent alpha-glucosidase inhibitor isolated from Salacia reticulata, and a good lead compound for an antidiabetic drug. It is essential to clarify the binding state of salacinol to alpha-glucosidase for efficient optimization study using structure-based drug design. Redocking simulations of two inhibitors, acarbose and casuarine whose complex structures are known, were performed to assure the appropriate docking pose prediction. The simulation reproduced both experimental binding states with accuracy. Then, using the same simulation protocol, the binding mode of salacinol and its derivatives has been predicted. Salacinol bound to the protein with a similar binding mode as casuarine, and the predicted structures could explain most of the structure-activity relationships of salacinol derivatives. (C) 2010 Elsevier Ltd. All rights reserved.
• Ligand Shape Emerges in Solvent Dipole Ordering Region at Ligand Binding Site of Protein

  Katsumi Murata; Naoya Nagata; Isao Nakanishi; Kazuo Kitaura

  JOURNAL OF COMPUTATIONAL CHEMISTRY JOHN WILEY & SONS INC 31 (4) 791 - 796 0192-8651 2010/03 

  Solvent dipole ordering (SDO), introduced by Higo et al. (Proteins Struct Funct Genet 2000, 40, 193), is an entity that captures an aspect of hydration structure. We have studied SDO in the ligand binding site of two proteins (FK506 binding protein and dihydrofolate reductase) and found that the high SDO regions overlap significantly with the 3D structures of known inhibitors bound to the proteins. Thus, the SDO region might be used to predict the preferred molecular shape of ligands that bind to a protein. Based on this finding, we propose a novel docking procedure using model molecules that mimic the shape of the SDO region. To prove the validity of this approach, we performed a redocking experiment for p38 mitogen-activated protein kinase ligands using model molecules for search queries; we Succeeded in identifying the binding conformations and binding modes of known inhibitors. (C) 2009 Wiley Periodicals, Inc. J Comput Chem 31: 791-796, 2010
• Amide-pi Interactions Between Formamide and Benzene

  Yumi N. Imai; Yoshihisa Inoue; Isao Nakanishi; Kazuo Kitaura

  JOURNAL OF COMPUTATIONAL CHEMISTRY JOHN WILEY & SONS INC 30 (14) 2267 - 2276 0192-8651 2009/11 

  High-level ab initio calculations have been carried out using a formamide-benzene model system to evaluate amide-n interactions. The interaction energies were estimated as a sum of the CCSD(T) correlation contribution and the HF energy at the complete basis set limit, for the geometries of the model structures in the energy minimum obtained by potential energy surface (PES) scans. NH/pi geometry in it face-on Configuration Was found to be the most attractive among the various geometries considered, with interaction energy of -3.75 kcal/mol. An interaction energy of -2.08 kcal/mol was calculated for the stacked N/Center type geometry, where the nitrogen atom of formamide points directly toward the center of the aromatic ring. The weakest C=O/pi geometry. where a carbonyl oxygen atom points toward the plane of the aromatic ring, was found to have energy minimum at,in intermolecular distance of 3.67 angstrom from the PES, with a repulsive interaction energy less than 1 kcal/mol. However. if there are simultaneous attractive interactions with other parts of the molecule besides the amide group, the weak repulsion Could be easily overcome, to give a C=O/pi geometry interaction. (C) 2009 Wiley Periodicals, Inc. J Comput Chem 30: 2267-2276, 2009
• フラグメント分子軌道法によるタンパク質－リガンド複合体の相互作用解析とアフィニティ計算

  仲西 功; 北浦和夫

  次世代創薬テクノロジー、実践：インシリコ創薬の最前線 メディカルドゥ 84 - 89 2009/09
• Cl-pi Interactions in Protein-Ligand Complexes

  Yumi N. Imai; Yoshihisa Inoue; Isao Nakanishi; Kazuo Kitaura

  QSAR & COMBINATORIAL SCIENCE WILEY-V C H VERLAG GMBH 28 (8) 869 - 873 1611-020X 2009/08 

  A geometry analysis of Cl-pi interactions in protein-ligand complex crystal structures, showed two distinct geometries: "edge-on" approach of a Cl atom to a ring atom or C-C bond and "face-on" approach towards the ring centroid, with an average interatomic distance of 3.6 angstrom. The interaction energies were estimated as a sum of the CCSD(T) correlation contribution and the Hartree-Fock energy at the complete basis set limit, for the geometries of the benzene-chlorohydrocarbon model structures at the energy minimum obtained by potential energy surface scans using RMP2(FC)/cc-pVTZ. The calculated Cl-pi interaction energy was -2.01 kcal/mol, and the dispersion force was found to be the major source of attraction. We also discuss the geometry flexibility in Cl-pi interactions.
• Structural insight into human CK2 alpha in complex with the potent inhibitor ellagic acid

  Yusuke Sekiguchi; Tetsuko Nakaniwa; Takayoshi Kinoshita; Isao Nakanishi; Kazuo Kitaura; Akira Hirasawa; Gozoh Tsujimoto; Toshiji Tada

  BIOORGANIC & MEDICINAL CHEMISTRY LETTERS PERGAMON-ELSEVIER SCIENCE LTD 19 (11) 2920 - 2923 0960-894X 2009/06 

  We determined the 2.35-angstrom crystal structure of a human CK2 catalytic subunit (referred to as CK2 alpha complexed with the ATP-competitive, potent CK2 inhibitor ellagic acid. The inhibitor binds to CK2 alpha with a novel binding mode, including water-mediated hydrogen bonds. This structural information may support discovery of potent CK2 inhibitors. (C) 2009 Elsevier Ltd. All rights reserved.
• Detailed electronic structure studies revealing the nature of protein-ligand binding.

  仲西 功; 北浦和夫; ドミトリ フェドロフ

  The fragment molecular orbital method. Practical applications to large molecular systems. CRC Press 2009/05
• Binding Free Energy Calculations of Adenosine Deaminase Inhibitor and the Effect of Methyl Substitution in Inhibitors

  Takahiro Kosugi; Isao Nakanishi; Kazuo Kitaura

  JOURNAL OF CHEMICAL INFORMATION AND MODELING AMER CHEMICAL SOC 49 (3) 615 - 622 1549-9596 2009/03 

  The binding affinity of an inhibitor is often improved ten times or more by introducing a simple substituent, such as a methyl group or a chlorine atom. We have investigated this phenomenon in the case of adenosine deaminase (ADA) inhibitors using molecular dynamics (MD) simulations and binding free energy calculations, by the linear interaction energy (LIE) method. For MD simulations, the coordination bond parameters and partial charges of atoms around the zinc ion in ADA have been determined by referring to ab initio MO calculations. The calculated binding free energies for seven inhibitors agreed well with the experimental ones, with a maximum error of 1.2 kcal/mol. The effect of methyl substitution in inhibitor molecules was examined on the basis of MD trajectories. It is suggested that the increase in binding affinity is caused by both van der Waals stabilizations by amino acid residues in contact with the introduced methyl group and through favored overall interactions with surrounding residues in the binding pocket.
• Structure of human protein kinase CK2 alpha 2 with a potent indazole-derivative inhibitor

  Tetsuko Nakaniwa; Takayoshi Kinoshita; Yusuke Sekiguchi; Toshiji Tada; Isao Nakanishi; Kazuo Kitaura; Yamato Suzuki; Hiroaki Ohno; Akira Hirasawa; Gozoh Tsujimoto

  ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY AND CRYSTALLIZATION COMMUNICATIONS WILEY-BLACKWELL PUBLISHING, INC 65 (65) 75 - 79 1744-3091 2009/02 

  Casein kinase 2 (CK2) is a serine/threonine kinase that functions as a heterotetramer composed of two catalytic subunits (CK2 alpha 1 or CK2 alpha 2) and two regulatory subunits (CK2 beta). The two isozymes CK2 alpha 1 and CK2 alpha 2 play distinguishable roles in healthy subjects and in patients with diseases such as cancer, respectively. In order to develop novel CK2 alpha 1-selective inhibitors, the crystal structure of human CK2 alpha 2 (hCK2 alpha 2) complexed with a potent CK2 alpha inhibitor which binds to the active site of hCK2 alpha 2 was determined and compared with that of human CK2 alpha 1. While the two isozymes exhibited a high similarity with regard to the active site, the largest structural difference between the isoforms occurred in the beta 4-beta 5 loop responsible for the CK2 alpha-CK2 beta interface. The top of the N-terminal segment interacted with the beta 4-beta 5 loop via a hydrogen bond in hCK2 alpha 2 but not in hCK2 alpha 1. Thus, the CK2 alpha-CK2 beta interface is a likely target candidate for the production of selective CK2 alpha 1 inhibitors.
• Cluster Hydration Model for Binding Energy Calculations of Protein-Ligand Complexes

  Katsumi Murata; Dmitri G. Fedorov; Isao Nakanishi; Kazuo Kitaura

  JOURNAL OF PHYSICAL CHEMISTRY B AMER CHEMICAL SOC 113 (3) 809 - 817 1520-6106 2009/01 

  We present a new model for predicting the binding affinity in protein-ligand complexes based on an explicit solvent treatment. The model is referred to as the cluster hydration model. Test calculations were performed on complexes of FK506-binding protein (FKBP) and its six ligands. The calculated binding energies had a good correlation with experimental binding affinities; the correlation coefficient r(2) was 0.93. Moreover, we examined the competition between the residue-ligand interactions and the desolvation energies of residues. The results suggested that, for the stabilization of the complexes in solution, the contributions of nonpolar residues at the binding site are larger than those of charged and polar ones because the electrostatic interaction energies between the residues and the ligand were mostly canceled by the desolvation penalties.
• Conformational change of adenosine deaminase during ligand-exchange in a crystal

  Takayoshi Kinoshita; Toshiji Tada; Isao Nakanishi

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ACADEMIC PRESS INC ELSEVIER SCIENCE 373 (1) 53 - 57 0006-291X 2008/08 

  Adenosine deaminase (ADA) perpetuates chronic inflammation by degrading extracellular adenosine which is toxic for lymphocytes. ADA has two distinct conformations: open form and closed form. From the crystal structures with various ligands, the non-nucleoside type inhibitors bind to the active site occupying the critical water-binding-position and sustain the open form of apo-ADA. In contrast, substrate mimics do not occupy the critical position, and induce the large conformational change to the closed form. However, it is difficult to predict the binding of (+)-erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), as it possesses characteristic parts of both the substrate and the non-nucleoside inhibitors. The crystal structure shows that EHNA binds to the open form through a novel recognition of the adenine base accompanying conformational change from the closed form of the PR-ADA complex in crystalline state. (C) 2008 Published by Elsevier Inc.
• Cl-pi interactions in protein-ligand complexes

  Yumi N. Imai; Yoshihisa Inoue; Isao Nakanishi; Kazuo Kitaura

  PROTEIN SCIENCE WILEY-BLACKWELL 17 (7) 1129 - 1137 0961-8368 2008/07 

  During systematic analysis of nonbonded contacts in protein-ligand complexes derived from crystal structures in the Protein Data Bank, Cl-pi interactions have been found, not only in the well-documented serine proteases but also, to a lesser extent, in other proteins. From geometric analysis of such Cl-pi interactions in the crystal structures, two distinct geometries were found: the "edge-on'' approach of a Cl atom to a ring atom or C-C bond and the "face-on'' approach toward the ring centroid with an average interatomic distance of 3.6 angstrom. High-level ab initio calculations using benzene-chlorohydro-carbon model systems elucidated that the calculated Cl-pi interaction energy is -2.01 kcal/mol, and the dispersion force is the major source of attraction. We also discussed the geometric flexibility in Cl-pi interactions and a relationship between the intensity of the pi density in an aromatic ring and the interaction position of the Cl atom.
• New progressing crystallization technology of membrane protein and introduction of pharamaceutical innovation value chain

  Tsuyoshi Inoue; Hiroaki Adachi; Satoshi Murakami; Kazufumi Takano; Hiroyoshi Matsumura; Yusuke Mori; Yoshifumi Fukunishi; Haruki Nakamura; Takayoshi Kinoshita; Isao Nakanishi; Yasushi Okuno; Satoshi Minakata; Shinji Shimojo; Tsuneaki Sakata

  Yakugaku Zasshi The Pharmaceutical Society of Japan 128 (4) 497 - 505 0031-6903 2008/04 [Refereed]
   

  We have recently established a Pharamaceutical Innovation Value Chain in collaboration with the SOSHO project (http://www.so-sho.jp) and BioGrid Project (http://www.biogrid.jp/) to accelerate new drug development. The SOSHO project provides novel crystallization technology with laser-irradiation and stirring growth methods, and the BioGrid Project is developing the software necessary for the in silico screening of promising drugs and the simulation of biological responses to proteins. In this paper, we report the recent research work on the crystallization of membrane proteins and the development of a method for in silico drug discovery. © 2008 The Pharmaceutical Society of Japan.
• Molecular recognition mechanism of FK506 binding protein: An all-electron fragment molecular orbital study

  Isao Nakanishi; Dmitri G. Fedorov; Kazuo Kitaura

  PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS WILEY-BLACKWELL 68 (1) 145 - 158 0887-3585 2007/07 [Refereed]
   

  The fragment molecular orbital (FMO) method has enabled electronic structure calculations and geometry optimizations of very large molecules with ab initio quality. We applied the method to four FK506 binding protein (FKBP) complexes (denoted by their PDB codes 1fkb, 1fkf, 1fkg, and 1fki) containing rapamycin, FK506, and two synthetic ligands. The geometries of reduced complex models were optimized at the restricted Hartree-Fock (FMO-RHF) level using the 3-21G basis set, and then for a better estimate of binding, the energetics were refined at a higher level of theory (2nd order Moller-Plesset perturbation theory FMO-MP2 with the 6-31G* basis set). Thus, obtained binding energies were -103.9 (-82.0), -102.2 (-69.2), -70.1 (-57.7), and -71.3 (-55.3) kcal/mol for 1fkb, 1fkf, 1fkg, and 1fki, respectively, where the correlation contribution is given in parentheses. The results show that the electron correlation contribution to binding is extremely important, and it accounts for 70-80% of the binding energy. The molecular recognition mechanism of FKBP was analyzed in detail based on the FMO-pair interactions between protein residues and the ligands. Solvation effects on the protein-ligand binding were estimated using the Poisson-Boltzmann/surface area model.
• Binding affinity prediction of non-peptide inhibitors of HIV-1 protease using COMBINE model introduced from peptide inhibitors.

  Nakamura S; Nakanishi I; Kitaura K

  Bioorganic & medicinal chemistry letters 16 (24) 6334 - 6337 0960-894X 2006/12 [Refereed]
  
• 2P417 Prediction of hydrogen-bonding sites between Protein and Ligand by Molecular Dynamics Simulation(46. Water and bio-molecule,Poster Session,Abstract,Meeting Program of EABS & BSJ 2006)

  Murata Katsumi; Nagata Naoya; Nakanishi Isao; Kitaura Kazuo

  Seibutsu Butsuri The Biophysical Society of Japan General Incorporated Association 46 (2) S400  2006
• Structural Basis of Compound Recognition by Adenosine Deaminase

  Takayoshi Kinoshita; Isao Nakanishi; Tadashi Terasaka; Masako Kuno; Nobuo Seki; Masaichi Warizaya; Hiroyoshi Matsumura; Tsuyoshi Inoue; Kazuhumi Takano; Hiroaki Adachi; Yusuke Mori; Takashi Fujii

  Biochemistry American Chemical Society (ACS) 44 (31) 10562 - 10569 0006-2960 2005/08 

  Structural snapshots corresponding to various states enable elucidation of the molecular recognition mechanism of enzymes. Adenosine deaminase has two distinct conformations, an open form and a closed form, although it has so far been unclear what factors influence adaptation of the alternative conformations. Herein, we have determined the first nonligated structure as an initial state, which was the open form, and have thereby rationally deduced the molecular recognition mechanism. Inspection of the active site in the nonligated and ligated states indicated that occupancy at one of the water-binding positions in the nonligated state was highly significant in determining alternate conformations. When this position is empty, subsequent movement of Phe65 toward the space induces the closed form. On the other hand, while occupied, the overall conformation remains in the open form. This structural understanding should greatly assist structure-oriented drug design and enable control of the enzymatic activity.
• 3P134 Ab initio fragment MO calculations of whole protein-ligand complexes: FK506 binding protein with high affinity ligands

  Nakanishi I.; Fedorov Dmitri; Kitaura K.

  Seibutsu Butsuri The Biophysical Society of Japan General Incorporated Association 45 S237  2005
• 1P043 Theoretical calculation of binding free energy and binding mode for Adenosine Deaminase inhibitor

  Kosugi T.; Nakanishi I.; Kitaura K.

  Seibutsu Butsuri The Biophysical Society of Japan General Incorporated Association 45 S42  2005
• A Highly Potent Non-Nucleoside Adenosine Deaminase Inhibitor: Efficient Drug Discovery by Intentional Lead Hybridization

  Tadashi Terasaka; Takayoshi Kinoshita; Masako Kuno; Isao Nakanishi

  Journal of the American Chemical Society 126 (1) 34 - 35 0002-7863 2004/01 

  We disclose herein the rapid discovery of the first highly potent (Ki = 7.7 nM) non-nucleoside adenosine deaminase (ADA) inhibitor based on the rational hybridization of two structurally distinct leads. Two micromolar inhibitors were discovered by a parallel rational design and random screening program, and individual crystal structures of bovine ADA in complexation with these inhibitors revealed several unknown binding sites and distinct binding modes. Using this information as the starting point, highly effective lead hybridization was achieved in only two structure-based drug design iterations. The conceptual approach illustrated by this example promises to be broadly useful in the search for new chemical entities and can contribute greatly to improve the overall efficiency and speed of drug discovery. Copyright © 2004 American Chemical Society.
• True interaction mode of porcine pancreatic elastase with FR136706, a potent peptidyl inhibitor

  Takayoshi Kinoshita; Isao Nakanishi; Akihiro Sato; Toshiji Tada

  Bioorganic and Medicinal Chemistry Letters 13 (1) 21 - 24 0960-894X 2003/01 [Refereed]
   

  The crystal structure of porcine pancreatic elastase (PPE) complexed with a potent peptidyl inhibitor, FR136706, was solved at 2.2 Å resolution. FR136706 fits snugly into the extended active site pocket. The benzene moiety of FR136706 induced dramatic movement of the side chain moiety of Arg217 and both moieties formed a π-π interaction, which has never been found previously in structures of PPE complexed with inhibitors. This novel interaction mode may lead to design of new types of inhibitors. © 2002 Elsevier Science Ltd. All rights reserved.
• Structure of porcine pancreatic elastase complexed with FR901277, a novel macrocyclic inhibitor of elastases, at 1.6 Å resolution

  Isao Nakanishi; Takayoshi Kinoshita; Akihiro Sato; Toshiji Tada

  Biopolymers John Wiley & Sons Inc 53 (5) 434 - 445 0006-3525 2000/04 [Refereed]
   

  Human leukocyte elastase (HLE) is a serine protease that contributes to tissue destruction in various disease states-for example, in emphysema. FR901277 is a natural product isolated from the culture filtrate of Streptomyces resistomicificus and is a potent inhibitor of both HLE and porcine pancreatic elastase (PPE). FR901277 consists of four normal amino acids and three unusual amino acids, and is a unique bicyclic peptide compound. The crystal structure of PPE complexed with FR901277 has been determined at 1.6 Å resolution. The Oγ atom of Ser-195 in PPE did not form a covalent bond with FR901277, but formed a hydrogen bond with the Nε atom of His-57. On the other hand, the portion from L-Orn(1) through dehydroxyThr(3) in FR901277 formed an antiparallel β-sheet structure with the backbone of the active site in PPE. The S4 through S2' binding subsites in PPE were all occupied by the hydrophobic side chains of the inhibitor molecule. Especially, the ethylidene moiety of FR901277 occupied the S1 specific pocket, indicating a CH/π interaction. In addition, the isopropyl side chain of L-Val(7) was located at the enzyme surface between the S2 and S1' pockets with several van der Waals contacts. However, the amino acid (4) residue was not involved in a significant interaction with PPE. Comparison of inhibitor structures in different environments showed that FR901277 has a highly rigid bicyclic framework however, it can slightly change its conformation according to the circumstances. The binding mode of FR901277 at the active site of PPE was directly applicable to that in HLE, after consideration of induced fit. The structure of the PPE-FR901277 complex provided much information regarding potential sites for modification of the physicochemical properties of FR901277. (C) 2000 John Wiley and Sons, Inc.
• Molecular structure of FR901277, a novel inhibitor of human leukocyte elastase, and its binding mode simulation

  Isao Nakanishi; Takayoshi Kinoshita; Toshiji Tada; Takashi Fujita; Hiroshi Hatanaka; Akihiro Sato

  Bioorganic and Medicinal Chemistry Letters 9 (16) 2397 - 2402 0960-894X 1999/08 [Refereed]
   

  X-ray crystal structure analysis of FR901277, a novel inhibitor of human leukocyte elastase, was performed and revealed that the lipophilic side chains are located towards the outside of the molecule. Binding simulation using computational methods showed that these lipophilic moieties could bind to the hydrophobic binding pockets of HLE.
• Studies on Cerebral Protective Agents. IX. Synthesis of Novel 1,2,3,4-Tetrahydroisoquinolines as N-Methyl-D-aspartate Antagonists.

  OHKUBO Mitsuru; KUNO Atsushi; KATSUTA Kiyotaka; UEDA Yoshiko; SHIRAKAWA Kiyoharu; NAKANISHI Hajime; NAKANISHI Isao; KINOSHITA Takayoshi; TAKASUGI Hisashi

  Chemical and Pharmaceutical Bulletin The Pharmaceutical Society of Japan 44 (1) 95 - 102 0009-2363 1996 

  A series of 1, 2, 3, 4-tetrahydroisoquinoline derivatives were synthesized and evaluated for anticonvulsant activity against intracerebro-ventriculas (i.c.v.) N-methyl-D-aspartate (NMDA)-induced seizures in mice. Among these compounds, (+)-1-methyl-1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline hydrochloride ((+)-1a, FR115427) was the most effective anticonvulsant, and also protected CA1 hippocampal neurons from ischemia-induced neuronal degeneration in rats at 32 mg/kg i.p. In addition, (+)-1a showed anti-hypoxic activity in mice at 3.2-32 mg/kg i.p. The absolute configuration at the C-1 position of the isoquinoline ring was determined to be S by a single-crystal X-ray analysis of (+)-1a (+)-di-p-toluoyl-D-tartrate. Structure-activity relationships with regard to the anticonvulsant activity of this series of compounds are discussed, and the three-dimensional structures of (S)-(+)-1a and MK801 are compared.
• Agents for the Treatment of Overactive Detrusor. VIII. Synthesis and Pharmacological Properties of 4,4-Diphenyl-2-cycloalkenylamines Including FK584 and 3,3- or 4,4-Diphenylcycloalkylamines.

  TANIGUCHI Kiyoshi; OKUMURA Kazuo; TAKE Kazuhiko; TSUBAKI Kazunori; TERAI Takao; NAKANISHI Isao; SHIOKAWA Youichi

  Chemical and Pharmaceutical Bulletin The Pharmaceutical Society of Japan 43 (1) 71 - 77 0009-2363 1995 

  This article describes the synthesis of 4, 4-diphenyl-2-cycloalkenylamines (3, 5a) including FK584 (S(-)-3a) and 3, 3- or 4, 4-diphenylcycloalkylamines (2, 4, 5b), and their inhibitory activities against detrusor contraction. The order of inhibitory activity (i.v.) of the N-tert-butylamine derivatives against urinary bladder rhythmic contraction in rats was as follows : S(-)-4, 4-diphenyl-2-cyclopentenylamine (FK584, S(-)-3a)>4, 4-diphenylcyclohexylamine (5b)=R(-)-3, 3-diphenylcyclopentylamine (R(-)-4)≥3, 3-diphenylcyclobutylamine (2)≥terodiline hydrochloride (HCl)(1)=RS(±)-4, 4-diphenyl-2-cyclohexenylamine (5a)>R(+)-4, 4-diphenyl-2-cyclopentenylamine (R(+)-3a)≥S(+)-3, 3-diphenylcyclopentylamine (S(+)-4). Although the inhibitory activity of FK584 and compounds R(-)-4 and 5b against detrusor contraction in vitro induced with KCl in guinea-pigs was less potent than that of terodiline HCl, their inhibitory activities against detrusor contractions in vitro induced by electrical field stimulation and carbachol were more potent than those of terodiline HCl.

Books etc

• 大地からの贈り物サラシア

  仲西功 (ContributorPP176-185)メディカルレビュー社 2018
• くすりをつくる研究者の仕事

  仲西功 (Joint work第5章)化学同人 2017/03
• わかりやすい物理化学 第2版

  仲西 功 (Joint work)廣川書店 2010/09
• コンピュータで薬を創ろう

  仲西 功 (Joint work)ケイディーネオブック 2009/06
• インシリコ創薬化学－ゲノム情報から創薬へ－

  仲西 功 (Joint work)京都廣川書店 2008/07
• 新しい薬をどう創るか

  仲西功 (Joint work第4章)講談社ブルーバックス 2007/04

Conference Activities & Talks

• Comparative Binding Energy 解析法を用いたNek2阻害剤のSBDD

  中村 真也; 西脇 敬二; 田辺 有香; 長岡 綾; 仲西 功

  第47回 構造活性相関シンポジウム  2019/12
• プリン骨格を有するCK2阻害剤の構造活性相関－微小な構造変換による結合様式の大きな変化－

  河津 有貴; 中川 愛理; 吉岡 賢司; 中村 真也; 西脇 敬二; 露口 正人; 木下 誉富; 仲西 功

  第47回 構造活性相関シンポジウム  2019/12
• Pyrazole骨格を有するCK2阻害剤の構造活性相関研究～窒素置換による物性・活性改善の検討～

  奥村 政輝; 中西 伸介; 西脇 敬二; 中村 真也; 大石 真也; 大野 浩章; 仲西 功

  第47回 構造活性相関シンポジウム  2019/12
• Comparative Binding Energy （COMBINE）解析法を用いたNek2阻害剤の設計、合成とその評価

  西脇 敬二; 中村 真也; 田辺 有香; 長岡 綾; 仲西 功

  第37回メディシナルケミストリーシンポジウム  2019/11
• 高選択的CK2a1阻害剤創出に向けた構造知見

  露口 正人; 仲庭 哲津子; 平澤 明; 仲西 功; 木下 誉富

  日本結晶学会 令和元年（2019年）度年会  2019/11
• β-シクロデキストリン-フェノバルビタールおよびシクロバルビタール複合体 形成時の熱力学プロファイルの解析  [Not invited]

  仲西 功; 酒井 優香; 本田 悠佳; 西野 菜月; 谷口 奈津子; 佐藤 真紀; 神山 匡; 西脇 敬二

  第55回熱測定討論会  2019/10
• Crystal structure of CK2a1 complexed with 5IOD.

  Masato Tsuyuguchi; Tetsuko Nakaniwa; Masaki Sawa; Isao Nakanishi; Takayoshi Kinoshita

  International Symposium on Diffraction Structure Biology 2019  2019/10
• pyrazole骨格を有するCK2阻害剤の構造活性相関研究 ―フッ素導入による活性および溶解性の変化―  [Not invited]

  釘宮 将也; 山口 諒; 中村 真也; 西脇 敬二; 仲西 功

  第69回 日本薬学会関西支部大会  2019/10
• プリン骨格を有するCK2阻害剤の構造活性相関研究―プリン骨格の互変異性の検討―

  河津 有貴; 中川 愛理; 吉岡 賢司; 中村 真也; 西脇 敬二; 露口 正人; 木下 誉富; 仲西 功

  第69回 日本薬学会関西支部大会、2019.10.12  2019/10
• Pyrazole骨格を有するCK2阻害剤の窒素スキャンによる構造活性・物性相関研究  [Not invited]

  奥村 政輝; 中西 伸介; 西脇 敬二; 中村 真也; 大石 真也; 大野 浩章; 仲西 功

  第69回 日本薬学会関西支部大会  2019/10
• ヘテロ環アゾ化合物－金属錯体を用いたシアン化物イオンの選択的比色分析  [Not invited]

  森川 泰裕; 八坂 直幸; 岡田 悠登; 井田 博之; 塩見 和孝; 西脇 敬二; 仲西 功; 鈴木 茂生

  日本分析化学会 第68年会  2019/09
• SBDDと計算化学－少ない計算資源で－  [Invited]

  仲西 功

  第19回FMO研究会  2019/09
• 基礎薬学科目の知識を臨床へつなぐ新しい学修システム構築の試み?実務実習実施前の学生に対する効果の検証?

  大内 秀一; 松野 純男; 和田 哲幸; 伊藤 栄次; 前川 智弘; 多賀 淳; 細見 光一; 大鳥 徹; 仲西 功; 川﨑 直人; 岩城 正宏

  第4回薬学教育学会大会  2019/08
• RAGEを標的とした化学療法誘起末梢神経障害治療薬の探索 in silicoドラッグ・リプロファイリング/リポジショニングからのアプローチ  [Not invited]

  脇谷 航平; 関口 富美子; 坪田 真帆; 中村 真也; 仲西 功; 川畑 篤史

  PAIN RESEARCH  2018/06  日本疼痛学会
  
• AzelastineはRAGEが関与する化学療法誘起末梢神経障害の発症を抑制する―ドラッグ・リプロファイリング/リポジショニング研究からの知見  [Not invited]

  脇谷航平; 関口富美子; 坪田真帆; 中村真也; 仲西功; 川畑篤史

  日本薬理学会近畿部会プログラム・要旨集  2018
• 高選択性CK2a1阻害薬の創出を目指したhemateinの作用機序の解明  [Not invited]

  露口 正人; 仲庭 哲津子; 仲西 功; 木下 誉富

  第46回構造活性相関シンポジウム  2018  大阪
• プリン骨格を有する新規CK2阻害剤の設計、合成と活性測定  [Not invited]

  吉岡 賢司; 中川 愛理; 谷口 誠哉; 露口 正人; 木下 誉富; 西脇 敬二; 中村 真也; 仲西 功

  第36回メディシナルケミストリーシンポジウム  2018  京都
• スフィンゴシンキナーゼ阻害剤開発を目指したJaspine B誘導体の合成と構造活性相関研究  [Not invited]

  宮川 貴吏; 井貫 晋輔; 本田 真歩; 中村 真也; 仲西 功; 藤井 信孝; 大石 真也; 大野 浩章

  第36回メディシナルケミストリーシンポジウム  2018  京都
• プリン骨格を有するCK2阻害剤における置換基位置の変換による結合様式の大きな変化  [Not invited]

  河津 有貴; 中川 愛理; 吉岡 賢司; 西脇 敬二; 中村 真也; 露口 正人; 木下 誉富; 仲西 功

  第68回 日本薬学会近畿支部総会・大会  2018  姫路
• ピラゾール骨格を有する新規CK2阻害剤の窒素スキャンによる構造活性相関研究  [Not invited]

  西尾 政輝; 中西 伸介; 西脇 敬二; 中村 真也; 露口 正人; 木下 誉富; 大石 真也; 大野 浩章; 仲西 功

  第68回 日本薬学会近畿支部総会・大会  2018  姫路
• 3Dプリンタを用いた医薬品分子模型の作成  [Not invited]

  佐々木 郁人; 仲西 功; 松野 純男; 大星 直樹

  第3回日本薬学教育学会大会  2018  東京
• 阻害剤誘導により現れたCK2a1の新規創薬標的ポケット  [Not invited]

  露口 正人; 仲西 功; 木下 誉富

  第18回タンパク質科学会年会  2018  新潟
• RAGEを標的とした化学療法誘起末梢神経障害治療薬の探索： In silicoドラッグ・リプロファイリング/リポジショニングからのアプローチ  [Not invited]

  脇谷 航平; 関口 富美子; 坪田 真帆; 中村 真也; 仲西 功; 川畑 篤史

  第40回日本疼痛学会  2018  長崎
• AzelastinはRAGEが関与する化学療法誘起末梢神経障害の発症を抑制する − ドラッグ・リプロファイリング／リポジショニング研究からの知見  [Not invited]

  脇谷 航平; 関口 富美子; 坪田 真帆; 中村 真也; 仲西 功; 川畑 篤史

  日本薬理学会第133回近畿部会  2018  広島
• SDO-VS法の精度向上研究：擬似分子の構成要素の検討  [Not invited]

  中村 真也; 北吉 駿; 仲西 功

  日本薬学会第138年会  2018  金沢
• プリン骨格を有する新規CK2阻害剤の構造活性相関研究  [Not invited]

  中川 愛理; 吉岡 賢司; 露口 正人; 木下 誉富; 中村 真也; 西脇 敬二; 仲西 功

  日本薬学会第138年会  2018  金沢
• リガンド間の類似性を考慮したCK2阻害剤の結合様式予測  [Not invited]

  谷口 誠哉; 津田 真佑; 露口 正人; 木下 誉富; 中村 真也; 仲西 功

  日本薬学会第138年会  2018  金沢
• Pd触媒を用いたTHF環構築によるJaspine B位置異性体の合成研究  [Not invited]

  宮川 貴吏; 本田 真歩; 中村 真也; 仲西 功; 井貫 晋輔; 大石 真也; 大野 浩章

  日本薬学会第138年会  2018  金沢
• HPCを活用した医薬品設計研究  [Not invited]

  仲西 功

  第1回近畿大学生物理工学部HPCシンポジウム  2018  和歌山
• HydroxychavicolをシードとしたXO阻害化合物の探索研究  [Not invited]

  西脇敬二; 出口貴浩; 大東可苗; 畑悠佑; 中村真也; 村田和也; 松田秀秋; 仲西功

  日本薬学会年会要旨集(CD-ROM)  2017
• ATP 部位及びアロステリック部位に結合するCK2α1 阻害剤  [Not invited]

  露口 正人; 仲西 功; 木下 誉富

  平成29年度日本結晶学会年会  2017  広島
• プリン骨格を有する化合物をシードとする新規CK2阻害剤の構造活性相関研究  [Not invited]

  中川 愛理; 吉岡 賢司; 露口 正人; 木下 誉富; 中村 真也; 西脇 敬二; 仲西 功

  日本薬学会近畿支部大会  2017  神戸
• CK 2a1-hemateinの結合を変化させる間接的要因  [Not invited]

  露口 正人; 平澤 明; 仲庭 哲津子; 櫻井 淳史; 仲西 功; 木下 誉富

  2017年度 日本蛋白質科学会年会  2017  仙台
• Hydroxychavicol をシードとした XO 阻害化合物の探索研究  [Not invited]

  西脇 敬二; 出口 貴浩; 大東 可苗; 畑 悠佑; 中村 真也; 村田 和也; 松田 秀秋; 仲西 功

  日本薬学会第137年会  2017  仙台
• バーチャルスクリーニング法により得られた化合物の結合様式の妥当性の評価  [Not invited]

  難波 佑輔; 中村 真也; 木下 誉富; 仲西 功

  日本薬学会第137年会  2017  仙台
• Crystal structure of CK2α2 in the new crystal form. 8th International Conference on Protein Kinase CK2  [Not invited]

  Masato Tsuyuguchi; Tetsuko Nakaniwa; Isao Nakanishi; Takayoshi Kinoshita

  8th International Conference on Protein Kinase CK2  2016  Homburg (Germany)
• Homology modeling of CCR4 and its evaluation based on the structure-activity relationship  [Not invited]

  Keiji Nishiwaki; Masashi Fujimoto; Shinya Nakamura; Isao Nakanishi

  21st EuroQSAR  2016  Verona (Italy)
• Evaluation of predicted binding structures of virtual screening hit compounds.  [Not invited]

  Isao Nakanishi; Yusuke Namba; Shinya Nakamura; Takayoshi Kinoshita

  21st EuroQSAR  2016  Verona (Italy)
• Different binding modes of apigenin in homologous proteins, human CK2α and maize CK2α.  [Not invited]

  Shinya Nakamura; Atsushi Sakurai; Takayoshi Kinoshita; Isao Nakanishi

  21st EuroQSAR  2016  Verona (Italy)
• Solvent Dipole Orderingの創薬への応用研究  [Not invited]

  中村 真也; 木村 翔拓; 北吉 駿; 仲西 功

  第10回分子科学討論会  2016  神戸
• His160 のコンホメーション変化と hematein による ATP 非拮抗型 CK2α1 阻害の関係  [Not invited]

  露口 正人; 平澤 明; 仲庭 哲津子; 櫻井 淳史; 仲西 功; 木下 誉富

  第16回日本蛋白質科学会年会  2016  福岡
• 基礎薬学分野の知識定着を志向した参加型学修システム構築の試み  [Not invited]

  大内 秀一; 松野 純男; 和田 哲幸; 仲西 功; 前川 智弘; 多賀 淳; 伊藤 栄次; 大鳥 徹; 川? 直人; 西田 升三

  日本薬学会第136年会  2016  横浜
• CK2サブタイプ間で異なるhemateinの相互作用様式の解明  [Not invited]

  露口 正人; 平澤 明; 仲庭 哲津子; 櫻井 淳史; 仲西 功; 木下 誉富

  2015年度量子ビームサイエンスフェスタ  2016  つくば
• 高選択性阻害剤の創出を目指したCK2a1およびCK2a2の構造解析  [Not invited]

  露口 正人; 平澤 明; 櫻井 淳史; 仲西 功; 木下 誉富

  第5回バイオメディカルフォーラム  2016  大阪
• CK2 α2の高分解能X線結晶構造解析  [Not invited]

  露口 正人; 仲庭 哲津子; 仲西 功; 木下 誉富

  日本結晶学会平成28年度年会  2015  水戸
• CK2 サブタイプ間で異なる四環性化合物の阻害作用機序の解明  [Not invited]

  露口 正人; 平澤 明; 仲庭 哲津子; 櫻井 淳史; 仲西 功; 木下 誉富

  2015  大阪
• Structural basis for producing CK2α1-specific inhibitors: Crystal structures of hematein with CK2α1 and CK2α2  [Not invited]

  露口 正人; 平澤 明; 仲庭 哲津子; 櫻井 淳史; 仲西 功; 木下 誉富

  第43回構造活性相関シンポジウム  2015  新潟
• CK2サブタイプ間で異なるhemateinの阻害作用メカニズムの解明  [Not invited]

  露口 正人; 平澤 明; 仲庭 哲津子; 櫻井 淳史; 仲西 功; 木下 誉富

  第15回日本タンパク質科学会年会  2015  徳島
• クロスメタセシス反応を利用したスフィンゴシンキナーゼ阻害剤の創製研究  [Not invited]

  本田 真歩; 宮垣 潤; 吉光 佑二; 岩田 顕; 大槻 和裕; 丸山 透; 中村 真也; 仲西 功; 大石 真也; 大野 浩章; 藤井 信孝

  日本薬学会第135年会  2015  神戸
• Binding pose prediction of Xantine oxidase inhibitor hydroxychavicol and drug design of its analogues.  [Not invited]

  International Symposium on Medicinal Chemistry 2014  2014  Lisbon  International Symposium on Medicinal Chemistry 2014
  
• Identification of protein kinase CK2 inhibitors by the solvent ordering virtual screening method.  [Not invited]

  International Symposium on Medicinal Chemistry 2014  2014  Lisbon  International Symposium on Medicinal Chemistry 2014
  
• Computer-aided design of novel alpha-glucosidase inhibitors based on salacinol derived from Salacia reticulate of Ayurvetic traditional medicine.  [Not invited]

  International Symposium on Medicinal Chemistry 2014  2014  Lisbon  International Symposium on Medicinal Chemistry 2014
  
• Species-dependent variation in the structure of CK2a-apigenin complex.  [Not invited]

  23rd Congress and General Assembly of the International Union of Crystallography  2014  Montreal  23rd Congress and General Assembly of the International Union of Crystallography
  
• Binding mode analysis of protein kinase CK2 inhibitors with a purine scaffold.  [Not invited]

  CBI Annual Meeting 2014  2014  Tokyo  CBI Annual Meeting 2014
  
• アカデミアシーズからのin silicoドラッグデザイン研究  [Not invited]

  仲西 功

  第356回CBI学会研究講演会  2014  大阪
• 結合自由エネルギーを指標としたProtein kinase CK2阻害剤のデザインと構造活性相関  [Not invited]

  中西 伸介; 岡田 裕規; 森脇 寛智; 西脇 敬二; 中村 真也; 木下 誉富; 大石 真也; 大野 浩章; 藤井 信孝; 仲西 功

  第37回情報化学討論会  2014  豊橋
• 構造活性相関解析に基づくXO阻害剤Hydroxychavicolの結合様式推定  [Not invited]

  大東 可苗; 西脇 敬二; 中村 真也; 出口 貴浩; 村田 和也; 松田 秀秋; 仲西 功

  第32回メディシナルケミストリーシンポジウム  2014  神戸
• スフィンゴシンキナーゼ阻害活性を有するJaspine B誘導体の構造活性相関研究  [Not invited]

  本田 真歩; 宮垣 潤; 吉光 佑二; 岩田 顕; 大槻 和裕; 丸山 透; 中村 真也; 仲西 功; 大石 真也; 大野 浩章; 藤井 信孝

  第32回メディシナルケミストリーシンポジウム  2014  神戸
• アーユルベーダ天然薬物“サラシア”由来salacinolをシードとするα-グルコシダーゼ阻害剤のin silico設計, 合成及びin vitro評価  [Not invited]

  田邉 元三; 松田 侑也; 筒井 望; 森川 敏生; 赤木 淳二; 二宮 清文; 仲西 功; 中村 真也; 吉川 雅之; 村岡 修

  第20回 天然薬物の開発と応用シンポジウム  2014  東京
• サラシア属植物含有α-グルコシダーゼ阻害活性成分salacinolおよびその類縁体の食後過血糖改善作用  [Not invited]

  森川 敏生; 赤木 淳二; 二宮 清文; 木内 恵理; 田邉 元三; 仲西 功; 中村 真也; 吉川 雅之; 村岡 修

  第20回 天然薬物の開発と応用シンポジウム  2014  東京
• a-グルコシダーゼ阻害活性物質salacinolおよびその誘導体の血糖値上昇抑制活性  [Not invited]

  森川 敏生; 木内 恵里; 赤木 淳二; 二宮 清文; 田邉 元三; 仲西 功; 中村 真也; 吉川 雅之; 村岡 修

  日本生薬学会第61回年会  2014  福岡
• タンパク質調整過程で結合したヒトCK2αリガンドのエントロピーを考慮した推定  [Not invited]

  櫻井 淳史; 中村 真也; 仲庭 哲津子; 関口 雄介; 曽我部 祐里; 木下誉富; 仲西 功

  日本薬学会第134年会  2014  熊本
• がん免疫療法のためのCOMBINE法を用いた高親和性ペプチド予測  [Not invited]

  中村 真也; 大村 梨恵; 仲西 功

  日本薬学会第134年会  2014  熊本
• Crystal structure of human CK2α at 1.04 ? resolution.  [Not invited]

  Takayoshi Kinoshita; Tetsuko Nakaniwa; Yusuke Sekiguchi; Yuri Sogabe; Atsushi Sakurai; Isao Nakanishi

  2013  Nagoya
• Structural insight into human CK2α with a flavonoid inhibitor.  [Not invited]

  Takayoshi Kinoshita; Yusuke Sekiguchi; Tetsuko Nakaniwa; Yuri Sogabe; Mai Tanaka; Kazuko Shimada; Shinya Nakamura; Isao Nakanishi

  The 12th Conference of the Asian Crystallographic Association  2013  Hong Kong  The 12th Conference of the Asian Crystallographic Association
  
• XO阻害活性を有するHydroxychavicolの結合様式推定と高活性化合物の探索  [Not invited]

  大東 可苗; 西脇 敬二; 中村 真也; 村田 和也; 松田 秀秋; 仲西 功

  日本薬学会第134年会  2013  熊本
• 連続縮環型分子の修飾による KSP 阻害剤の溶解性  [Not invited]

  竹内 智起; 大石 真也; 金田 雅仁; 大野 浩章; 中村 真也; 仲西 功; 山根 正敏; 澤田 潤一; 浅井 章良; 藤井 信孝

  第31回メディシナルケミストリーシンポジウム  2013  広島
• 骨粗鬆症治療薬を目指した選択的アンドロゲン受容体調節剤 (SARM) の創薬研究  [Not invited]

  永田 尚也; 古屋 和行; 小黒 奈央; 河合 健太郎; 山本 紀子; 根地嶋 宏昌; 大藪 有紀; 薩川 正広; 仲西 功; 井口 潔; 宮川 基則

  第31回メディシナルケミストリーシンポジウム  2013  広島
• a-グルコシダーゼ阻害剤の酵素阻害活性におけるヒトとラットの種差の計算化学的解析  [Not invited]

  島田 和子; 中村 真也; 田邉 元三; 村岡 修; 仲西 功

  第31回メディシナルケミストリーシンポジウム  2013  広島
• サラシノールを基点とする新規α-グルコシダーゼ阻害剤の構造活性相関および創出研究  [Not invited]

  中村 真也; 高平 和典; 島田 和子; 田邉 元三; 村岡 修; 仲西 功

  第41回構造活性相関シンポジウム  2013  兵庫
• SDOVS: A Solvent Dipole Ordering-based Method for Virtual Screening  [Not invited]

  永田 尚也; 村田 克美; 仲西 功; 北浦 和夫

  第41回構造活性相関シンポジウム  2013  兵庫
• タンパク質調整過程で結合したヒトCK2αリガンドの推定  [Not invited]

  櫻井 淳史; 中村 真也; 仲庭 哲津子; 関口 雄介; 曽我部 祐里; 木下 誉富; 仲西 功

  第41回構造活性相関シンポジウム  2013  兵庫
• α-Glucosidase 阻害剤, Salacinol の構造活性相関研究：3’ 位脂溶性化が活性に及ぼす効果  [Not invited]

  田邉 元三; 中村 真也; 筒井 望; 赤木 淳二; 森川 敏生; 二宮 清文; 仲西 功; 吉川 雅之; 村岡 修

  第5回食品薬学シンポジウム  2013  京都
• 金触媒を用いた三成分環化反応によるジヒドロピラゾールの合成とCK2阻害剤開発への応用  [Not invited]

  大野 浩章; 鈴木 大和; 侯 増; 呉 竜英; 仲西 功; 平澤 明; 大石 真也; 藤井 信孝

  複素環化学討論会  2013  岐阜
• CK2αキナーゼ−フラボノイド化合物の結合様式における種差  [Not invited]

  関口 雄介; 仲庭 哲津子; 曽我部 祐里; 田中 麻衣; 島田 和子; 中村 真也; 仲西 功; 木下 誉富

  日本結晶学会年会  2013  熊本
• α-グルコシダーゼ阻害剤, Salacinolの構造活性相関研究―トルイル酸型置換基による3’位疎水化の効果―  [Not invited]

  田邉 元三; 中村 真也; 國方 雄介; 筒井 望; 赤木 淳二; 森川 敏生; 二宮 清文; 仲西 功; 吉川 雅之; 村岡 修

  日本薬学会近畿支部大会  2013  京都  日本薬学会近畿支部
  
• ヒトとラットにおけるα-グルコシダーゼ阻害剤アカルボースの酵素阻害活性の種差の検討  [Not invited]

  島田 和子; 中村 真也; 高平 和典; 田邉 元三; 村岡 修; 仲西 功

  日本薬学会第133年会  2013  横浜  日本薬学会
  
• ヒトα-グルコシダーゼ触媒ドメイン群と阻害剤の横断的構造活性相関  [Not invited]

  中村 真也; 高平 和典; 田邉 元三; 村岡 修; 仲西 功

  日本薬学会第133年会  2013  横浜  日本薬学会
  
• Salacinol をシードとするスルホニウム塩型α-グルコシダーゼ阻害剤のin silico 設計、合成及び評価：3'位アルキル化の効果  [Not invited]

  田邉 元三; 國方 雄介; 中村 真也; 筒井 望; 赤木 淳二; 森川 敏生; 二宮 清文; 吉川 雅之; 仲西 功; 村岡 修

  日本薬学会第133年会  2013  横浜  日本薬学会
  
• 非経験的フラグメント分子軌道法を活用した高活性Protein Kinase CK2 阻害剤の設計  [Not invited]

  呉 竜英; 侯 増?; 木下 誉富; 武井 義則; 安江 美里; 三須 良介; 鈴木 大和; 中村 真也; 大野 浩章; 村田 克美; 北浦 和夫; 平澤 明; 大石 真也; 藤井 信孝; 仲西 功

  第40回構造活性相関シンポジウム  2012/11  岡崎
• Salacinol をシードとする新規α- グルコシダーゼ阻害剤の in silico 設計, 合成および評価  [Not invited]

  田邉 元三; 中村 真也; 筒井 望; 赤木 淳二; 森川 敏生; 二宮 清文; 仲西 功; 吉川 雅之; 村岡 修

  第30回メディシナルケミストリーシンポジウム  2012/11  東京
• 縮環型含窒素複素環の多様性指向型合成法を利用した新規CK2 阻害剤の設計と合成  [Not invited]

  直江 紗織; 鈴木 大和; 大石 真也; 武井 義則; 安江 美里; 三須 良介; 候 増; 呉 竜英; 仲西 功; 大野 浩章; 平澤 明; 藤井 信孝

  第30回メディシナルケミストリーシンポジウム  2012/11  東京
• Salacinolをシードとするスルホニウム塩型α-グルコシダーゼ阻害剤のin silico設計，合成及び評価  [Not invited]

  田邉 元三; 中村 真也; 國方 雄介; 土屋 聡史; 吉長 正絋; 筒井 望; 赤木 淳二; 森川 敏生; 二宮 清文; 仲西 功; 吉川 雅之; 村岡 修

  第19回天然薬物の開発と応用シンポジウム  2012/11  大阪
• 分子シミュレーションを用いたProtein Kinase CK2 阻害剤の活性予測  [Not invited]

  中西 伸介; 森脇 寛智; 中村 真也; 西脇 敬二; 仲西 功

  第62回日本薬学会近畿支部大会  2012/10  兵庫  日本薬学会近畿支部
  
• Salacinol をシードとするスルホニウム塩型α-グルコシダーゼ阻害剤のin silico 設計、合成及び評価  [Not invited]

  田邉 元三; 中村 真也; 國方 雄介; 土屋 聡史; 吉長 正絋; 筒井 望; 赤木 淳二; 森川 敏生; 二宮 清文; 仲西 功; 吉川 雅之; 村岡 修

  第62回日本薬学会近畿支部大会  2012/10  兵庫  日本薬学会近畿支部
  
• フェニルアゾール骨格を有する新規プロテインキナーゼCK2阻害剤の開発  [Not invited]

  侯 増; 大石 真也; 武井 義則; 安江 美里; 三須 良介; 鈴木 大和; 村田 克美; 北浦 和夫; 平澤 明; 辻本 豪三; 大野 浩章; 仲西 功; 中村 真也; 呉 竜英; 木下 誉富; 藤井 信孝

  第42回複素環化学討論会  2012/10  京都
• Binding energy estimation of CK2 inhibitors by the ab initio-based fragment molecular orbital method.  [Not invited]

  Tatsuhide Kure; Shinya Nakamura; Masayuki Kanemitsu; Katsumi Murata; Kazuo Kitaura; Takayoshi Kinoshita; Zengye Hou; Yamato Suzuki; Hiroaki Ohno; Shinya Oishi; Nobutaka Fujii; Yoshinori Takei; Misato Yasue; Ryosuke Misu; Akira Hirasawa; Gozoh Tsujimoto; Isao Nakanishi

  2012/09  Berlin
• SDOVS: A solvent dipole ordering-based method for virtual screening.  [Not invited]

  Naoya Nagata; Katsumi Murata; Isao Nakanishi; Kazuo Kitaura

  2012/09  Berlin
• ラット小腸由来α-グルコシダーゼのホモロジーモデリングとkotalanolとの複合体構造予測  [Not invited]

  島田 和子; 西脇 敬二; 中村 真也; 仲西 功

  第10回次世代を担う若手のためのフィジカル・ファーマフォーラム 京都  2012/08  京都
• 溶媒中における3(5)-Amino-5(3)-arylpyrazole誘導体の互変異性体存在比率の予測  [Not invited]

  呉 竜英; 櫻井 淳史; 西脇 敬二; 中村 真也; 仲西 功

  第10回次世代を担う若手のためのフィジカル・ファーマフォーラム 京都  2012/08  京都
• アザインドール骨格またはフェニルアゾール骨格を有する新規プロテインキナーゼCK2阻害剤の開発研究  [Not invited]

  侯 増カ; 大石 真也; 武井 義則; 安江 美里; 三須 良介; 鈴木 大和; 村田 克美; 北浦 和夫; 平澤 明; 辻本 豪三; 大野 浩章; 藤井 信孝; 仲西 功; 中村 真也; 呉 竜英; 木下 誉富

  第10回次世代を担う有機化学シンポジウム  2012/05  大阪
• LynおよびLckキナーゼの阻害剤との相互作用解析  [Not invited]

  宮野 菜央; 呉 竜英; 中村 真也; 中井 良子; 桐井 康行; 木下 誉富; 仲西 功; 多田 俊治

  日本結晶学会年会  2011/11  北海道  日本結晶学会
  
• FEP/TI法によるリガンド間のタンパク質結合自由エネルギー差の評価  [Not invited]

  中尾 佳人; 中村 真也; 仲西 功

  第34回情報化学討論会  2011/11  長崎
• MM/PBSA法によるCK2阻害剤ヘマテインの結合様式の予測  [Not invited]

  永松 和彦; 中村 真也; 木下 誉富; 平澤 明; 辻本 豪三; 仲西 功

  第34回情報化学討論会  2011/11  長崎
• α-Glucosidase阻害剤salacinolの3’位疎水化の活性に及ぼす効果  [Not invited]

  田邉 元三; 土屋 聡史; 筒井 望; 赤木 淳二; 中村 真也; 仲西 功; 吉川 雅之; 村岡 修

  第61回日本薬学会近畿支部大会  2011/10  兵庫  日本薬学会近畿支部
  
• Srcファミリーキナーゼ特異的阻害剤SU6656の選択性に関する計算化学的考察  [Not invited]

  呉 竜英; 中村 真也; 宮野 菜央; 多田 俊治; 多賀 淳; 仲西 功

  第９回次世代を担う若手のためのフィジカル・ファーマフォーラム 箱根  2011/09  神奈川
• α-Glucosidase阻害剤salacinolの構造活性相関：3' 位ベンジル化の効果  [Not invited]

  田邉 元三; 土屋 聡史; 筒井 望; 峯松 敏江; 赤木 淳二; 中村 真也; 仲西 功; 吉川 雅之; 村岡 修

  日本薬学会第132年会  2011/03  北海道  日本薬学会
  
• Phenylpyrazole誘導体の互変異性体の溶媒中における存在比率の予測  [Not invited]

  呉 竜英; 中村 真也; 仲西 功

  日本薬学会第132年会  2011/03  北海道  日本薬学会
  
• SDO情報を用いた新規なバーチャルスクリーニング法の開発  [Not invited]

  永田 尚也; 村田 克美; 仲西 功; 北浦 和夫

  日本薬学会第132年会  2011/03  北海道  日本薬学会
  
• 糸球体腎炎におけるCK2a特異的阻害効果の検討  [Not invited]

  安江 美里; 劉 寧; 武井 義則; 侯 増力; 鈴木 大和; 大野 浩明; 仲西 功; 木下 誉富; 村田 克美; 北浦 和夫; 平澤 明; 辻本 豪三

  日本薬学会第131年会  2011/03  静岡  日本薬学会
  
• 分子力場計算におけるCl-π相互作用パラメータの作成と分子動力学計算による検証  [Not invited]

  中尾 佳人; 中村 真也; 仲西 功

  日本薬学会第131年会  2011/03  静岡  日本薬学会
  
• マルターゼグルコアミラーゼのC末端側触媒ドメインにおけるコタラノールの結合様式の予測  [Not invited]

  高平 和典; 中村 真也; 村岡 修; 仲西 功

  日本薬学会第131年会  2011/03  静岡  日本薬学会
  
• CK2阻害剤Hemateinの結合様式の予測  [Not invited]

  永松 和彦; 中村 真也; 木下 誉富; 平澤 明; 辻本 豪三; 仲西 功

  日本薬学会第131年会  2011/03  静岡  日本薬学会
  
• MOEによるフラグメント分子軌道計算支援環境の開発  [Not invited]

  中村 真也; 仲西 功

  日本コンピュータ化学会 年会：2010秋季年会  2010/10  新潟  日本コンピュータ化学会 年会：2010秋季年会
   

  計算機資源の向上と計算手法の発達により、従来では困難であった高精度な分子軌道計算による相互作用解析が、タンパク質−薬物複合体などの巨大分子系においても一般化しつつある。これらの知見は、構造に基づくドラッグデザインに大きな知見をもたらすと期待がされており、特に古典的な力場計算では考慮していなかった、CH-O相互作用やCl-pi相互作用などが結合に寄与することが重要視されてきている。巨大分子系の分子軌道計算は、近似計算の方のひとつであるフラグメント分子軌道法（FMO法）によって行われることが多い。FMO法の利点は、単純に計算時間が短縮できるという点だけではなく、リガンドと各アミノ酸残基との相互作用など通常の分子軌道計算では求めることが困難な要素を得ることが可能であり、それにより力場法で行っていたことに近い感覚で解析が可能であるという点が挙げられる。 すでにFMO法に関するインターフェースはABINIT-MPなどいくつか存在し
• Binding mode prediction and analysis for salacinol derivatives as alpha-glucosidase inhibitors.  [Not invited]

  中村 真也; 仲西 功; 田邉 元三; 森川 敏生; 二宮 清文; 村岡 修; 高平和典; 坂野実加; 吉川雅之

  18th European QSAR symposium 2010  2010/09  Rhodes (Greece)  18th European QSAR symposium 2010
  
• サラシア属植物有効成分のドッキングスタディと構造活性相関  [Not invited]

  仲西 功

  第3回サラシア属植物シンポジウム  2010/08  東京  第3回サラシア属植物シンポジウム
  
• MOEを用いたGAMESS/FMO解析支援ツールの開発  [Not invited]

  中村 真也; 仲西 功

  MOEフォーラム2010  2010/07  東京  MOEフォーラム2010
   

  計算機資源の向上に伴い、タンパク質−薬物複合体などの巨大分子系においても高精度な分子軌道計算による相互作用解析が浸透しつつある。それにより、従来の古典的な力場計算では考慮していなかった、CH-O相互作用やCL-π相互作用などによる結合への寄与が明らかになってきている。しかし巨大分子系の分子軌道計算は、通常の計算方法では現実的な計算時間で解析を行うことが困難なため、近似計算の方のひとつであるフラグメント分子軌道法（FMO法）によって行われることが多い。FMO法の利点は、単純な計算時間の短縮できるという点だけではなく、アミノ酸残基ごとの相互作用など通常の分子軌道計算では求めることが困難な要素を得ることが可能であり、それにより力場法で行っていたことに近い感覚で解析が可能であるという点が挙げられる。 現在FMO法による計算が可能なツールとしてはGAMESSやABINIT-MP, PAICSなどが存在しており、GAMESS/FMOではFMO法の開発者らによる最新の
• 分子シミュレーションと構造活性相関  [Not invited]

  仲西 功

  構造活性フォーラム2010  2010/06  京都  構造活性フォーラム2010
  
• CK2阻害剤結合時の熱力学的プロファイル差に関する計算化学的考察  [Not invited]

  中村 真也; 仲西 功; 金光政幸; 仲庭哲津子; 木下誉富; 深田はるみ; 北浦和夫; 大野浩章; 鈴木大和; 平澤明; 辻本豪三

  日本薬学会第130年会  2010/03  岡山  日本薬学会第130年会
   

  【目的】新規に阻害剤を設計する際には、阻害剤の結合自由エネルギーを予測することが重要となる。本研究で用いたCK2阻害剤であるCC4791およびCC4820の結合自由エネルギーはほぼ同等であるが、小さな置換基変化（イソプロピル基とシクロペンチル基）にも関わらず、熱力学的プロファイル（エンタルピー・エントロピーの寄与度）が異なることが熱測定により観測されている。構造の差がどのような要因で熱力学的な差を生じさせているのか、計算化学的に考察を行った。 【方法】それぞれの複合体に対し、阻害剤の周囲25?に対し水分子を発生させた系で分子動力学（MD）計算を行い、このトラジェクトリーに対し溶媒効果を含めた相互作用計算を行った。また、阻害剤の結合状態と水中との運動性の差を解析するため、阻害剤を半径25?の球状の水分子クラスター中に配置した系でもMD計算を行い、置換基の二面角を中心に運動性を検討した。 【結果と考察】相互作用計算の結果、CC4
• salacia 属植物有効成分のα グルコシダーゼ結合様式の推定  [Not invited]

  高平和典; 中村 真也; 田邉 元三; 村岡 修; 仲西 功

  日本薬学会第130年会  2010/03  岡山  日本薬学会第130年会
   

  【目的】インドやスリランカの伝統医学アーユルヴェーダでは、Salacia属植物が糖尿病の特効薬として用いられている。本植物から単離されるチオ糖スルホニウム硫酸分子内塩構造を持つsalacinolやkotalanolは、？グルコシダーゼを阻害することによる糖吸収抑制作用を有しており、同メカニズムに基づく抗糖尿病薬であるacarboseやvogliboseに匹敵する？グルコシダーゼ阻害活性を有している。本研究では、これらの化合物のタンパク質結合構造をもとに新規阻害剤の設計をするために、両化合物のドッキングシミュレーションを実施した。 【方法】まず、？グルコシダーゼの１つであるマルターゼグルコアミラーゼのN末端側触媒ドメインとacarbose及びcasuarineとの複合体構造（PDBID：2QMJおよび3CTT）を再現できるドッキングシミュレーション条件を探索した。次にそのシミュレーション条件を用いて、salacinol及びkotalanolの結合様式を推定した。 【結果】結合シミュレーションの結果、salacinol及び
• サラシア属植物含有成分salacinolのαグルコシダーゼへの結合シミュレーション  [Not invited]

  仲西 功; 中村 真也; 高平和典

  第3回食品薬学シンポジウム  2009/11  大阪  第3回食品薬学シンポジウム
  
• 新規αグルコシダーゼ阻害剤探索へ向けたsalacinolの結合様式推定  [Not invited]

  仲西 功; 中村 真也; 高平和典

  第59回日本薬学会近畿支部大会  2009/10  大阪  第59回日本薬学会近畿支部大会
  
• α-グルコシダーゼと阻害剤との複合体の結晶化  [Not invited]

  仲西 功; 中村 真也; 大迫久晃; 山口亜佐子; 木下誉富; 多田俊治

  第3回食品薬学シンポジウム  2009/10  大阪  第3回食品薬学シンポジウム
  
• Conformational change of adenosine deaminase during ligand-exchange in crystal state.  [Not invited]

  木下誉富; 多田俊治; 仲西 功

  25th European Crystallographic Meeting  2009/08  Istanbul (Turkey)  25th European Crystallographic Meeting
  
• An approach for producing a CK2alpha inhibitor using X-ray, calculation and ITC.  [Not invited]

  関口雄介; 深田はるみ; 仲庭哲津子; 木下誉富; 多田俊治; 仲西 功; 中村 真也; 北浦和夫; 大野浩明; 鈴木大和; 平澤明; 辻本豪三

  25th European Crystallographic Meeting  2009/08  Istanbul (Turkey)  25th European Crystallographic Meeting
  
• サラシア属植物有効成分のin silico解析  [Not invited]

  仲西 功

  第2回サラシア属植物シンポジウム  2009/08  大阪  第2回サラシア属植物シンポジウム
  
• 新規腎炎治療薬創出へのX 線結晶構造解析：CK2αアイソフォーム間の1アミノ酸残基の差を狙った選択性獲得への挑戦  [Not invited]

  関口雄介; 木下誉富; 仲庭哲津子; 多田俊治; 仲西 功; 村田克美; 北浦和夫; 宮崎貴子; 平澤明; 辻本豪三

  第９回日本蛋白質科学会年会  2009/05  熊本  第９回日本蛋白質科学会年会
  
• 単結晶中で観測されたアデノシンデアミナーゼの構造変化  [Not invited]

  木下誉富; 多田俊治; 仲西 功

  第９回日本蛋白質科学会年会  2009/05  熊本  第９回日本蛋白質科学会年会
  
• Cluster Hydration Modelによる蛋白質の部分脱水和エネルギーの解析  [Not invited]

  村田克美; 北浦和夫; 仲西 功; ドミトリ フェドロフ

  日本薬学会第129年会  2009/03  京都  日本薬学会第129年会
  
• FMO 法によるカゼインキナーゼ2の分子認識機構解析  [Not invited]

  浅田直也; 北浦和夫; 仲西 功

  日本薬学会第129年会  2009/03  京都  日本薬学会第129年会
  
• カゼインキナーゼII アイソザイム選択的阻害化合物スクリーニング系の構築  [Not invited]

  宮崎貴子; 村田克美; 北浦和夫; 平澤明; 辻本豪三; 仲西 功; 仲庭哲子; 木下誉富

  日本薬学会第129年会  2009/03  京都  日本薬学会第129年会
  
• The effect of the electron correlation to the structure optimization by Fragment MO method  [Not invited]

  井上 雄貴; 中村 真也; 仲西 功; 北浦 和夫

  日本薬学会第129年会  2009/03  京都  日本薬学会第129年会
   

  【目的】タンパク質と低分子との結合親和力を高精度に計算することは、ターゲットの構造に基づく薬物設計を行うために最も重要な要素のひとつである。定量性に最も優れた非経験的分子軌道法を、タンパク質などの大きな系に適用する計算手法として、Fragment MO(FMO)法が開発されている。タンパク質のFMO法による計算はすでに浸透しつつあるが、一般的に、タンパク質と低分子との相互作用には分散力が大きく寄与することが、MP2レベルなどの電子相関を考慮したFMO法のエネルギー計算から明らかとなってきている。しかし相互作用を精密に計算する前段階である構造最適化は、計算コストの問題から電子相関を考慮しないHFレベルで計算されているのが現状である。本研究ではMP2レベルの計算が構造に与える影響について検討を行った。 【方法】GAMESS/FMOを用いて、FK506 Binding Protein(FKBP)とその4つの阻害剤との各複合体をFMO-MP2/6-31Gレベル、および比較のためにFMO-HF/3-21Gレベルで構造最
• An approach for producing a potent CK2？ inhibitor using X-ray and calorimetry analyses.  [Not invited]

  関口雄介; 深田はるみ; 仲庭哲津子; 木下誉富; 多田俊治; 仲西 功; 中村 真也; 北浦和夫; 大野浩明; 鈴木大和; 平澤明; 辻本豪三

  第38回構造活性相関シンポジウム  2008/11  神戸  第38回構造活性相関シンポジウム
  
• Theoretical study of geometry and molecular recognition mechanism of Casein Kinase 2？ (CK2？) with the FMO-MP2 method.  [Not invited]

  仲西 功; 浅田直也; 北浦和夫

  第38回構造活性相関シンポジウム  2008/11  神戸  第38回構造活性相関シンポジウム
  
• Docking-pose prediction by a receptor-based tailor-made scoring function  [Not invited]

  中村 真也; 仲西 功; 北浦 和夫

  8th China-Japan symposium on drug design and development  2008/10  Kobe (Japan)  8th China-Japan symposium on drug design and development
   

  バーチャルスクリーニングの高精度化のため、COMBINE解析法を応用した受容体特異的なスコア関数を考案した。バーチャルスクリーニングでは化合物の活性値予測と結合様式予測の両者が重要となるが、今回はその検証の一つとして、後者の結合様式予測に関して、HIV ptorease およびAdenosine deaminaseとその阻害薬を用いて予測が可能か検討した。 （英文）
• Analysis of interactions between Casein Kinase 2？ (CK2？) and its ligand using Fragment Molecular Orbital method.  [Not invited]

  浅田直也; 北浦和夫; 仲西 功

  European QSAR symposium 2008  2008/09  Uppsara (Sweden)  European QSAR symposium 2008
  
• Cl?π interactions in protein?ligand complexes.  [Not invited]

  今井友美; 北浦和夫; 仲西 功; 井上佳久

  European QSAR symposium 2008  2008/09  Uppsara (Sweden)  European QSAR symposium 2008
  
• Crystal structure of human CK2 alpha in complex with ellagic acid.  [Not invited]

  関口雄介; 仲庭哲津子; 木下誉富; 多田俊治; 仲西 功; 北浦和夫; 平澤明; 辻本豪三

  IUCr2008  2008/08  大阪  IUCr2008
  
• Quantum chemical calculation of protein-ligand interaction.  [Not invited]

  仲西 功

  XXth EFMC-ISMC  2008/08  Vienna (Austria)  XXth EFMC-ISMC
  
• Structure of the catalytic subunit of human protein kinase CK2alpha prime with a potent inhibitor.  [Not invited]

  仲庭哲津子; 関口雄介; 木下誉富; 多田俊治; 仲西 功; 北浦和夫; 平澤明; 辻本豪三

  IUCr2008  2008/08  大阪  IUCr2008
  

MISC

• Structure activity relationship study of ck2 inhibitors with a pyrazole scaffold by nitrogen scan

  奥村政輝; 中西伸介; 栗本泰奈; 西脇敬二; 中村真也; 大石真也; 大野浩章; 仲西功  日本薬学会年会要旨集(CD-ROM)  140th-  2020
• ヘテロ環アゾ化合物-金属錯体を用いたシアン化物イオンの選択的比色分析

  森川 泰裕; 八坂 直幸; 岡田 悠登; 井田 博之; 塩見 和孝; 西脇 敬二; 仲西 功; 鈴木 茂生; 京都府警科; 近畿大薬  日本分析化学会第68年会要旨集P3137  2019/09
• Structure-activity relationship study of CK2 inhibitors with a pyrazole scaffold by nitrogen scan

  奥村政輝; 中西伸介; 栗本泰奈; 西脇敬二; 中村真也; 大石真也; 大野浩章; 仲西功  構造活性相関シンポジウム講演要旨集  47th (CD-ROM)-  2019
• RAGEを標的とした化学療法誘起末梢神経障害治療薬の探索 in silicoドラッグ・リプロファイリング/リポジショニングからのアプローチ

  脇谷 航平; 関口 富美子; 坪田 真帆; 中村 真也; 仲西 功; 川畑 篤史  PAIN RESEARCH  33-  (2)  157  -157  2018/06
• AzelastineはRAGEが関与する化学療法誘起末梢神経障害の発症を抑制する―ドラッグ・リプロファイリング/リポジショニング研究からの知見

  脇谷航平; 関口富美子; 坪田真帆; 中村真也; 仲西功; 川畑篤史  日本薬理学会近畿部会プログラム・要旨集  133rd-  44  2018
• プリン骨格を有する新規CK2阻害剤の構造活性相関研究

  中川愛理; 吉岡賢司; 露口正人; 木下誉富; 中村真也; 西脇敬二; 仲西功  日本薬学会年会要旨集(CD-ROM)  138th-  ROMBUNNO.27PA‐pm097  2018
• HydroxychavicolをシードとしたXO阻害化合物の探索研究

  西脇敬二; 出口貴浩; 大東可苗; 畑悠佑; 中村真也; 村田和也; 松田秀秋; 仲西功  日本薬学会年会要旨集(CD-ROM)  137th-  ROMBUNNO.27PA‐am038  2017
• クロスメタセシス反応を利用したスフィンゴシンキナーゼ阻害剤の創製研究

  HONDA MAHO; MIYAGAKI JUN; YOSHIMITSU YUJI; IWATA AKIRA; OTSUKI KAZUHIRO; MARUYAMA TOORU; NAKAMURA SHIN'YA; NAKANISHI ISAO; OISHI SHIN'YA; ONO HIROAKI; FUJII NOBUTAKA  日本薬学会年会要旨集(CD-ROM)  135th-  ROMBUNNO.28S-AM13  2015
• スフィンゴシンキナーゼ阻害活性を有するJaspine B誘導体の構造活性相関研究

  HONDA MAHO; MIYAGAKI JUN; YOSHIMITSU YUJI; IWATA AKIRA; OTSUKI KAZUHIRO; MARUYAMA TOORU; NAKAMURA SHIN'YA; NAKANISHI ISAO; OISHI SHIN'YA; ONO HIROAKI; FUJII NOBUTAKA  メディシナルケミストリーシンポジウム講演要旨集  32nd-  119  2014/11
• サラシア属植物含有α‐グルコシダーゼ阻害活性成分salacinolおよびその類縁体の食後過血糖改善作用

  森川敏生; 赤木淳二; 二宮清文; 木内恵里; 田邉元三; 仲西功; 中村真也; 吉川雅之; 村岡修  天然薬物の開発と応用シンポジウム講演要旨集  20th-  75  -77  2014/11
• アーユルベーダ天然薬物“サラシア”由来salacinolをシードとするα‐グルコシダーゼ阻害剤のin silico設計,合成及びin vivo評価

  田邉元三; 松田侑也; 筒井望; 森川敏生; 赤木淳二; 二宮清文; 仲西功; 中村真也; 吉川雅之; 村岡修  天然薬物の開発と応用シンポジウム講演要旨集  20th-  72  -74  2014/11
• α‐グルコシダーゼ阻害活性物質salacinolおよびその誘導体の血糖値上昇抑制活性

  森川敏生; 木内恵里; 赤木淳二; 二宮清文; 田邉元三; 仲西功; 中村真也; 吉川雅之; 村岡修  日本生薬学会年会講演要旨集  61st-  235  -235  2014/08
• Binding free energy-guided design of Protein kinase CK2 inhibitors and structure-activity relationship analysis

  Nakanishi Shinsuke; Okada Hironori; Moriwaki Hirotomo; Nishiwaki Keiji; Nakamura Shinya; Kinoshita Takayoshi; Oishi Shinya; Ohno Hiroaki; Fujii Nobutaka; Nakanishi Isao  Proceedings of the Symposium on Chemoinformatics  2014-  (0)  P08  -P08  2014
• 連続縮環型分子の修飾によるKSP阻害剤の溶解性改善

  TAKEUCHI TOMOKI; OISHI SHIN'YA; KANEDA MASATO; ONO HIROAKI; NAKAMURA SHIN'YA; NAKANISHI ISAO; YAMANE MASAYOSHI; SAWADA JUN'ICHI; ASAI AKIRA; FUJII NOBUTAKA  メディシナルケミストリーシンポジウム講演要旨集  31st-  167  2013/11
• α‐グルコシダーゼ阻害剤,Salacinolの構造活性相関研究―トルイル酸型置換基による3’位疎水化の効果―

  田邉元三; 中村真也; 筒井望; 赤木淳二; 森川敏生; 二宮清文; 仲西功; 吉川雅之; 村岡修  メディシナルケミストリーシンポジウム講演要旨集  31st-  112  2013/11
• α‐グルコシダーゼ阻害剤の酵素阻害活性におけるヒトとラットの種差の計算化学的解析

  島田和子; 中村真也; 田邉元三; 村岡修; 仲西功  メディシナルケミストリーシンポジウム講演要旨集  31st-  84  2013/11
• サラシノールを基点とする新規α‐グルコシダーゼ阻害剤の構造活性相関および創出研究

  中村真也; 高平和典; 島田和子; 田邉元三; 村岡修; 仲西功  構造活性相関シンポジウム講演要旨集  41st-  33  -34  2013/10
• 金触媒を用いた三成分環化反応によるジヒドロピラゾールの合成とCK2阻害剤開発への応用

  ONO HIROAKI; SUZUKI YAMATO; HOU ZENGYE; KURE TATSUHIDE; NAKANISHI ISAO; HIRASAWA AKIRA; OISHI SHIN'YA; FUJII NOBUTAKA  複素環化学討論会講演要旨集  43rd-  353  -354  2013/10
• α‐Glucosidase阻害剤,Salacinolの構造活性相関研究:3’位脂溶性化が活性に及ぼす効果

  田邉元三; 中村真也; 筒井望; 赤木淳二; 森川敏生; 二宮清文; 仲西功; 吉川雅之; 村岡修  食品薬学シンポジウム講演要旨集  5th-  178  -180  2013/10
• ヒトとラットにおけるα‐グルコシダーゼ阻害剤アカルボースの酵素阻害活性の種差の検討

  島田和子; 中村真也; 高平和典; 田邉元三; 村岡修; 仲西功  日本薬学会年会要旨集(CD-ROM)  133rd-  (2)  ROMBUNNO.29AMB-164S  -310  2013/03
• ヒトα‐グルコシダーゼ触媒ドメイン群と阻害剤の横断的構造活性相関

  中村真也; 高平和典; 田邉元三; 村岡修; 仲西功  日本薬学会年会要旨集(CD-ROM)  133rd-  (2)  ROMBUNNO.29AMB-162  -309  2013/03
• Salacinolをシードとするスルホニウム塩型α‐グルコシダーゼ阻害剤のin silico設計,合成及び評価:3’位アルキル化の効果

  田邉元三; 國方雄介; 中村真也; 筒井望; 赤木淳二; 森川敏生; 二宮清文; 仲西功; 吉川雅之; 村岡修  日本薬学会年会要旨集(CD-ROM)  133rd-  ROMBUNNO.29K-AM06S  2013
• 非経験的フラグメント分子軌道法を活用した高活性Protein Kinase CK2阻害剤の設計

  GO RYUEI; KO ZOYO; KINOSHITA TAKAYOSHI; TAKEI YOSHINORI; YASUE MISATO; MISU RYOSUKE; SUZUKI YAMATO; NAKAMURA SHIN'YA; ONO HIROAKI; MURATA KATSUMI; KITAURA KAZUO; HIRASAWA AKIRA; OISHI SHIN'YA; FUJII NOBUTAKA; NAKANISHI ISAO  構造活性相関シンポジウム講演要旨集  40th-  30  -33  2012/11
• 縮環型含窒素複素環の多様性指向型合成反応の開発とCK2阻害剤の構造活性相関研究への応用

  NAOE SAORI; SUZUKI YAMATO; OISHI SHIN'YA; TAKEI YOSHINORI; YASUE MISATO; MISU RYOSUKE; HOU ZENGYE; KURE TATSUHIDE; NAKANISHI ISAO; ONO HIROAKI; HIRASAWA AKIRA; FUJII NOBUTAKA  メディシナルケミストリーシンポジウム講演要旨集  30th-  66  2012/11
• Salacinolをシードとする新規α‐グルコシダーゼ阻害剤のin silico設計,合成および評価

  田邉元三; 中村真也; 筒井望; 赤木淳二; 森川敏生; 二宮清文; 仲西功; 吉川雅之; 村岡修  メディシナルケミストリーシンポジウム講演要旨集  30th-  88  2012/11
• Salacinolをシードとするスルホニウム塩型α‐グルコシダーゼ阻害剤のin silico設計,合成及び評価

  田邉元三; 中村真也; 國方雄介; 土屋聡史; 吉長正紘; 筒井望; 赤木淳二; 森川敏生; 二宮清文; 吉川雅之; 仲西功; 村岡修  天然薬物の開発と応用シンポジウム講演要旨集  19th-  125  -127  2012/10
• フェニルアゾール骨格を有する新規プロテインキナーゼCK2阻害剤の開発

  HOU ZENGYE; OISHI SHIN'YA; TAKEI YOSHINORI; YASUE MISATO; MISU RYOSUKE; SUZUKI YAMATO; MURATA KATSUMI; KITAURA KAZUO; HIRASAWA AKIRA; TSUJIMOTO GOZO; ONO HIROAKI; NAKANISHI ISAO; NAKAMURA SHIN'YA; KURE TATSUHIDE; KINOSHITA TAKAYOSHI; FUJII NOBUTAKA  複素環化学討論会講演要旨集  42nd-  245  -246  2012/09
• アザインドール骨格またはフェニルアゾール骨格を有する新規プロテインキナーゼCK2阻害剤の開発研究

  HOU Z; OISHI SHIN'YA; TAKEI YOSHINORI; YASUE MISATO; MISU RYOSUKE; SUZUKI YAMATO; MURATA KATSUMI; KITAURA KAZUO; HIRASAWA AKIRA; TSUJIMOTO GOZO; ONO HIROAKI; FUJII NOBUTAKA; NAKANISHI ISAO; NAKAMURA SHIN'YA; KURE RYUEI; KINOSHITA TAKAYOSHI  次世代を担う有機化学シンポジウム講演要旨集  10th-  50  -51  2012/05
• α‐Glucosidase阻害剤salacinolの構造活性相関:3’位ベンジル化の効果

  田邉元三; 土屋聡史; 筒井望; 峯松敏江; 赤木淳二; 中村真也; 仲西功; 吉川雅之; 村岡修  日本薬学会年会要旨集  132nd-  (2)  164  -164  2012/03
• マルターゼーグルコアミラーゼのC末端側触媒ドメインにおけるコタラノールの結合様式の予測

  高平和典; 中村真也; 村岡修; 仲西功  日本薬学会年会要旨集  131st-  (4)  126  2011/03
• salacia属植物有効成分のαグルコシダーゼ結合様式の推定

  高平和典; 中村真也; 田邉元三; 村岡修; 仲西功  日本薬学会年会要旨集  130th-  (2)  258  2010/03
• The Trial of Drug Discovery using the In-Silico Screening Methods Developed by Pharmaceutical Innovation Value Chain

  INOUE Tsuyoshi; MATSUMURA Hiroyoshi; ADACHI Hiroaki; MORI Yusuke; TAKANO Kazufumi; MURAKAMI Satoshi; FUKUNISHI Yoshifumi; NAKAMURA Haruki; KINOSHITA Takayoshi; NAKANISHI Isao; OKUNO Yasushi; MINAKATA Satoshi; MIKAMI Yoshiaki; SAKUMA Toshihiro; KITAJIMA Masato; FUKUOKA Yoshitada; TAKADA Toshikazu; SAKATA Tsuneaki  Nihon Kessho Gakkaishi  52-  (1)  89  -94  2010
• Design of anti-allergic inhibitors for human hematopoietic prostaglandin D synthase

  Hiroshi Kikuchi; Yuji Kado; Hiroyoshi Matsumura; Yoshifumi Fukunishi; Takayoshi Kinoshita; Yasushi Okuno; Isao Nakanishi; Seiji Minakata; Tsuneaki Sakata; Kohsuke Aritake; Yoshihiro Urade; Tsuyoshi Inoue  ACTA CRYSTALLOGRAPHICA A-FOUNDATION AND ADVANCES  64-  C344  -C344  2008  [Refereed]
  
• Drug development value chain constructed by collaboration between the SOSHO project and the NPO BIOGRID

  Tsuyoshi Inoue; Yuji Kado; Keiji Tokuoka; Hiroyoshi Matsumura; Yasushi Kai; Yusuke Mori; Hiroaki Adachi; Kazufumi Takano; Satoshi Murakami; Yoshifumi Fukunishi; Haruki Nakamura; Takayoshi Kinoshita; Isao Nakanishi; Yasushi Okuno; Seiji Minakata; Tsuneaki Sakata  AIP Conference Proceedings  902-  85  -88  2007
• Department of Theoretical Drug Design, Graduate School of Pharmaceutical Sciences, Kyoto University

  仲西 功  MEDCHEM NEWS  16-  (3)  6  -9  2006/08
• P-5 Exploration of New Anti-HIV Leads Inhibiting Nuclear Export of Rev Protein on the Basis of Mechanism of Action

  Tamura Satoru; Shiomi Atsushi; Todo S.; Kaneko Masafumi; Shioda Tatsuo; Kimura Tominori; Yoshida Minoru; Nagata Naoya; Nakanishi Isao; Kitaura Kazuo; Murakami Nobutoshi  Symposium on the Chemistry of Natural Products, symposium papers  48-  253  -258  2006
• Binding Affinity Prediction by Linear Response Approximation Considered Ligand Internal Energy

  Kosugi Takahiro; Nakanishi Isao; Kitaura Kazuo  Proceedings of the Symposium on Chemoinformatics  2005-  JP15  -JP15  2005
• 技術解説 計算化学的手法による新規活性化合物の探索

  仲西 功  生産と技術 = Manufacturing & technology / 大阪大学生産技術研究会 編  54-  (4)  15  -19  2002
• Studies on Cerebral Protective Agents. VIII. 1α) Synthesis of 2-Aminothiazoles and 2-Thiazolecarboxamides with Anti-anoxic Activity

  OHKUBO Mitsuru; KUNO Atsushi; NAKANISHI Isao; TAKASUGI Hisashi  Chemical & pharmaceutical bulletin  43-  (9)  1497  -1504  1995/09

Awards & Honors

• 平成17年度 日本薬学会･医薬化学部会賞
  

Research Grants & Projects

• Development of Novel Drug Discovery Technologies for Target Proteins with Elusive Molecular Basis

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2015/04 -2018/03 

  Author : Fujii Nobutaka; NAKANISHI Isao; OISHI Shinya

   

  Through the structure-activity relationship study of cyclic pentapeptide CXCR7 ligands, a number of potent and highly selective ligands were identified. The binding modes and structural requirements of some representative ligands were revealed by molecular modeling studies. Efficient synthetic approaches for alkaloid scaffolds were developed, which can be applicable to medicinal chemistry studies. Furthermore, several inhibitory molecules with unique biological and/or functional properties were identified against sphingosine kinases, CK2 kinases and NK3 receptor via the structure-activity relationship studies.
• Development of a method to discover high affinity ligands using molecular dynamics simulation

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2010 -2012 

  Author : NAKANISHI Isao; KITAURA Kazuo

   

  The free energy perturbation (FEP)/Thermodynamic integration (TI) methods were applied to explore high affinity ligands with a small structural change to a known ligand. By changing various calculation conditions, affinity differences among protein kinase CK2 ligands could be reproduced with high accuracy. Possibly novel potent ligands for CK2 protein were discovered by exhaustive prediction of synthetic feasible ligands. The optimized calculation condition gives good reproducibility and this prediction method is useful in drug discovery.
• DEVELOPMENT OF MULTILEVEL FRAGMENT MOLECULAR ORBITAL METHOD

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2008 -2010 

  Author : KITAURA Kazuo; NAKANISHI Isao

   

  We have develped the multilevel fragment molecular orbital method in which effective fragment potential (EFP), molecular mechanics (MM), and polarizable continuum solvent model (PCM) have been interfaced with the the fragment molecular orbital (FMO) method. The method facilitates geometry optimizations and molecular dynamics simulations of large molecular systems and is expected to be usuful in simulation studies of biomolecules.
• Development of the prediction method of ligand binding affinity in SBDD

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2006 -2008 

  Author : NAKANISHI Isao; KITAURA Kazuo

   

  フラグメント分子軌道(FMO)法による相互作用エネルギーを用いた薬物活性予測法の開発を行った。水和エネルギーにPCM法用いたFMO/PCM法は、パラメータを用いないab initioな活性(結合自由エネルギー)予測法にもかかわらず、実験値のオーダーの再現性には非常に優れていた。今後、分子運動やエントロピー等を考慮することにより、実用レベルでの予測精度を達成できるものと期待される。

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https://researchmap.jp/isayan