仲西 功(ナカニシ イサオ)

薬学部 創薬科学科教授

Last Updated :2024/11/22

■教員コメント

コメント

計算化学的手法を駆使し、スーパーコンピュータなどを用いながらタンパク質の構造に基づく医薬品設計研究を行なっています。製薬会社で約20年創薬研究に携わっていました。

■研究者基本情報

学位

  • 博士(薬学)(大阪大学)

研究キーワード

  • 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   

現在の研究分野(キーワード)

計算化学的手法を駆使し、スーパーコンピュータなどを用いながらタンパク質の構造に基づく医薬品設計研究を行なっています。製薬会社で約20年創薬研究に携わっていました。

研究分野

  • ライフサイエンス / 薬系化学、創薬科学
  • ナノテク・材料 / 基礎物理化学

■経歴

経歴

  • 2008年04月 - 現在  近畿大学薬学部教授
  • 2003年08月 - 2008年03月  京都大学薬学部助教授/准教授
  • 1985年04月 - 2003年07月  藤沢薬品工業(株)

学歴

  • 1983年04月 - 1985年03月   大阪大学大学院   薬学研究科   薬品化学専攻
  • 1979年04月 - 1983年03月   大阪大学   薬学部   製薬科学科

委員歴

  • 2009年04月 - 現在   奈良県立奈良高等学校   SSH運営委員
  • - 現在   日本薬学会構造活性相関部会   常任幹事
  • 2015年04月 - 2020年03月   日本薬学会   代議員
  • 2013年03月 - 2017年03月   日本薬学会近畿支部   常任幹事
  • 2015年 - 2016年   科学研究費補助金審査員
  • 2015年 - 2015年   日本薬学会学会賞選考委員

■研究活動情報

受賞

  • 平成17年度 日本薬学会・医薬化学部会賞

論文

  • Shinya Nakamura; Keiji Nishiwaki; Masato Tsuyuguchi; Takayoshi Kinoshita; Shinya Oishi; Hiroaki Ohno; Isao Nakanishi
    Chemical and Pharmaceutical Bulletin 72 9 776 - 780 2024年09月
  • Fumihiro Ishikawa; Shinya Nakamura; Isao Nakanishi; Genzoh Tanabe
    Journal of peptide science : an official publication of the European Peptide Society 30 3 e3545  2024年03月 
    Nonribosomal peptide synthetases (NRPSs) biosynthesize nonribosomal peptide (NRP) natural products, which belong to the most promising resources for drug discovery and development because of their wide range of therapeutic applications. The results of genetic, biochemical, and bioinformatics analyses have enhanced our understanding of the mechanisms of the NRPS machinery. A major goal in NRP biosynthesis is to reprogram the NRPS machinery to enable the biosynthetic production of designed peptides. Reprogramming strategies for the NRPS machinery have progressed considerably in recent years, thereby increasing the yields and generating modified peptides. Here, the recent progress in NRPS reprogramming and its application in peptide synthesis are described.
  • Keiji Nishiwaki; Shiori Nakatani; Shinya Nakamura; Kenji Yoshioka; Eri Nakagawa; Masato Tsuyuguchi; Takayoshi Kinoshita; Isao Nakanishi
    RSC Medicinal Chemistry 2024年 
    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...
  • Katsuki Takashima; Shinya Nakamura; Maiko Nagayama; Shinsuke Marumoto; Fumihiro Ishikawa; Weijia Xie; Isao Nakanishi; Osamu Muraoka; Toshio Morikawa; Genzoh Tanabe
    RSC Advances 14 7 4471 - 4481 2024年 
    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.
  • Keiji Nishiwaki; Shinya Nakamura; Kenji Yoshioka; Eri Nakagawa; Shiori Nakatani; Masato Tsuyuguchi; Takayoshi Kinoshita; Isao Nakanishi
    Chemical and Pharmaceutical Bulletin 71 7 558 - 565 2023年07月 
    プロテインキナーゼ CK2 (CK2) は、がん、腎炎、COVID-19感染症などに対する治療薬開発の標的タンパク質である。これまでに、SDO-VS法を用いて、プリン骨格を含む新しい候補 CK2α 阻害剤を同定している。ドッキング計算の結果、化合物11は、多くのCK2阻害剤とCK2との複合体結晶構造において観察された水分子を排除して結合していることを示唆し、それはX線結晶構造解析の結果から証明された。構造活性相関データからデザインした化合物12はIC50が4.3μMを示した。
  • Tatsuo Akaki; Shinya Nakamura; Keiji Nishiwaki; Isao Nakanishi
    Chemical and Pharmaceutical Bulletin 71 4 299 - 306 2023年02月 [査読有り]
  • Shinya Nakamura; Tatsuo Akaki; Keiji Nishiwaki; Midori Nakatani; Yuji Kawase; Yuki Takahashi; Isao Nakanishi
    Journal of Computational Chemistry 44 7 824 - 831 2022年11月 [査読有り]
  • Asaka Ikeda; Masato Tsuyuguchi; Daisuke Kitagawa; Masaaki Sawa; Shinya Nakamura; Isao Nakanishi; Takayoshi Kinoshita
    Biochemical and biophysical research communications 630 30 - 35 2022年11月 
    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.
  • Yasuhiro Morikawa; Keiji Nishiwaki; Shigeo Suzuki; Kazutaka Shiomi; Isao Nakanishi
    Forensic Toxicology 40 2 393 - 399 2022年07月
  • Yasuhiro Morikawa; Keiji Nishiwaki; Shigeo Suzuki; Mitsuhiro Kinoshita; Isao Nakanishi
    Analytical Sciences 38 2 437 - 442 2022年02月 
    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.
  • 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年08月 
    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.
  • 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年02月 
    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.
  • 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 11 6 3221 - 3225 2021年 

    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.

  • Fumihiro Ishikawa; Hinano Kitayama; Shinya Nakamura; Katsuki Takashima; Isao Nakanishi; Genzoh Tanabe
    Chemical & pharmaceutical bulletin 69 2 222 - 225 2021年 
    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.
  • Yasuhiro Morikawa; Miku Hirabara; Keiji Nishiwaki; Shigeo Suzuki; Isao Nakanishi
    Materials Advances 2 18 6104 - 6111 2021年 
    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-.
  • Yasuhiro Morikawa; Keiji Nishiwaki; Shigeo Suzuki; Naoyuki Yasaka; Yuto Okada; Isao Nakanishi
    The Analyst 145 23 7759 - 7764 2020年11月 
    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.
  • Masato Tsuyuguchi; Tetsuko Nakaniwa; Akira Hirasawa; Isao Nakanishi; Takayoshi Kinoshita
    Bioorganic & medicinal chemistry letters 30 2 126837 - 126837 2020年01月 [査読有り]
     
    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.
  • Fumihiro Ishikawa; Maya Nohara; Shinya Nakamura; Isao Nakanishi; Genzoh Tanabe
    Biochemistry DOI: 10.1021/acs.biochem.9b00748 59 4 351 - 363 2020年01月 [査読有り]
     
    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.
  • Tsuyuguchi M; Nakaniwa T; Sawa M; Nakanishi I; Kinoshita T
    Acta crystallographica. Section F, Structural biology communications 75 Pt 7 515 - 519 2019年07月 [査読有り]
     
    © 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.
  • 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 2019年05月 [査読有り]
     
    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.
  • Nishiwaki K; Ohigashi K; Deguchi T; Murata K; Nakamura S; Matsuda H; Nakanishi I
    Chemical & Pharmaceutical Bulletin 66 7 741 - 747 2018年07月 [査読有り]
     
    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.
  • Miyagawa Takashi; Inuki Shinsuke; Honda Maho; Nakamura Shinya; Nakanishi Isao; Fujii Nobutaka; Oishi Shinya; Ohno Hiroaki
    TETRAHEDRON 74 15 1802 - 1809 2018年04月 [査読有り]
  • Shinya Nakamura; Hayao Kitayoshi; Isao Nakanishi
    J. Comp. Aided Chem. 18 149 - 158 公益社団法人 日本化学会・情報化学部会 2017年10月 [査読有り]
     
    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.
  • Shinya Nakamura; Rie Ohmura; Isao Nakanishi
    Chem-Bio Informatics Journal 17 93 - 102 2017年09月 [査読有り]
     
    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年06月 [査読有り]
  • 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 25 12 3046 - 3052 2017年06月 [査読有り]
     
    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.
  • 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 14 5 1528 - 1537 2017年05月 [査読有り]
     
    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.
  • Tanabe G; Xie W; Balakishan G; Amer MF; Tsutsui N; Takemura H; Nakamura S; Akaki J; Ninomiya K; Morikawa T; Nakanishi I; Muraoka O
    Bioorganic & medicinal chemistry 24 16 3705 - 3715 2016年08月 [査読有り]
     
    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.
  • 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 24 5 1136 - 1141 2016年03月 [査読有り]
     
    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.
  • 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 96 396 - 404 2015年05月 [査読有り]
     
    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.
  • Dmitri G. Fedorov; Naoya Asada; Isao Nakanishi; Kazuo Kitaura
    ACCOUNTS OF CHEMICAL RESEARCH 47 9 2846 - 2856 2014年09月 [査読有り]
     
    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.
  • Tomoki Takeuchi; Shinya Oishi; Masato Kaneda; Ryosuke Misu; Hiroaki Ohno; Jun-ichi Sawada; Akira Asai; Shinya Nakamura; Isao Nakanishi; Nobutaka Fujii
    BIOORGANIC & MEDICINAL CHEMISTRY 22 12 3171 - 3179 2014年06月 [査読有り]
     
    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.
  • 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 5 5 566 - 571 2014年05月 [査読有り]
     
    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.
  • Kengo Miyamoto; Fumihiro Ishikawa; Shinya Nakamura; Yutaka Hayashi; Isao Nakanishi; Hideaki Kakeya
    BIOORGANIC & MEDICINAL CHEMISTRY 22 8 2517 - 2528 2014年04月 [査読有り]
     
    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.
  • Kinoshita T; Nakaniwa T; Sekiguchi Y; Sogabe Y; Sakurai A; Nakamura S; Nakanishi I
    Journal of synchrotron radiation 20 Pt 6 974 - 979 2013年11月 [査読有り]
     
    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.
  • Zengye Hou; Shinya Oishi; Yamato Suzuki; Tatsuhide Kure; Isao Nakanishi; Akira Hirasawa; Gozoh Tsujimoto; Hiroaki Ohno; Nobutaka Fujii
    ORGANIC & BIOMOLECULAR CHEMISTRY 11 20 3288 - 3296 2013年 [査読有り]
     
    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.
  • Tanabe G; Matsuoka K; Yoshinaga M; Xie W; Tsutsui N; A Amer MF; Nakamura S; Nakanishi I; Wu X; Yoshikawa M; Muraoka O
    Bioorganic & medicinal chemistry 20 21 6321 - 6334 2012年11月 [査読有り]
     
    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.
  • Nakamura S; Takahira K; Tanabe G; Muraoka O; Nakanishi I
    Open Journal of Medicinal Chemistry 2 3 50 - 60 2012年09月
  • Naoya Asada; Dmitri G. Fedorov; Kazuo Kitaura; Isao Nakanishi; Kenneth M. Merz
    JOURNAL OF PHYSICAL CHEMISTRY LETTERS 3 18 2604 - 2610 2012年09月 [査読有り]
     
    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.
  • Naoya Nagata; Kentaro Kawai; Isao Nakanishi
    JOURNAL OF CHEMICAL INFORMATION AND MODELING 52 8 2257 - 2264 2012年08月 [査読有り]
     
    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,
  • 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 55 6 2899 - 2903 2012年03月 [査読有り]
     
    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.
  • 田邉 元三; 吉川 雅之; 村岡 修; 中村 真也; 吉長 正絋; 筒井 望; Balakishan Gorre; 赤木 淳二; 森川 敏生; 二宮 清文; 仲西 功
    天然有機化合物討論会講演要旨集 54 0 285 - 290 天然有機化合物討論会実行委員会 2012年 
    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]
  • 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 10 25 4907 - 4915 2012年 [査読有り]
     
    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.
  • Tanabe G; Nakamura S; Tsutsui N; Balakishan G; Xie W; Tsuchiya S; Akaki J; Morikawa T; Ninomiya K; Nakanishi I; Yoshikawa M; Muraoka O
    Chemical communications (Cambridge, England) 48 69 8646 - 8648 2012年 [査読有り]
     
    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.
  • 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 356 1-2 97 - 105 2011年10月 [査読有り]
     
    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.
  • 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年04月 [査読有り]
  • 永松 和彦; 中村 真也; 木下 誉富; 平澤 明; 辻本 豪三; 仲西 功
    情報化学討論会講演要旨集 2011 P2 - P2 公益社団法人 日本化学会 2011年 
    カゼインキナーゼ2 (CK2) は、癌、感染症、腎炎等の疾患の標的タンパク質と考えられており、多様な骨格を有する阻害剤が報告されている。これらの多くはCK2の補酵素であるATPの結合部位に結合し、ATP競合型の阻害様式を示す。一方、アカミノキ由来の阻害剤ヘマテインは、ATP結合部位に加え、他の部位にも結合し混合阻害型の様式を示すことが報告されているが、その結合様式は明らかにされていない。そこで、ヘマテインのCK2への結合様式をドッキングシミュレーションとMM/PBSA法により予測した。
  • 中尾 佳人; 中村 真也; 仲西 功
    情報化学討論会講演要旨集 2011 P20 - P20 公益社団法人 日本化学会 2011年 
    FEP/TI法により生体高分子化合物と複数リガンド間の結合自由エネルギー差を予測する事を目的として、活性化血液凝固因子?]a(F?]a)とその阻害剤との複合体で検討を行った。F?]a複合体には分子力学モデルでは正しく評価できない非古典的な分子間相互作用が結合に重要であり、それを踏まえ様々な条件でFEP/TI計算を行った。その結果について報告する。
  • 村田克美; 永田尚也; 北浦和夫; 仲西 功
    Journal of Computational Chemistry 31 15 2714 - 2722 Wiley 2010年11月 
    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.
  • 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
    Bioorganic and Medicinal Chemistry Letters 20 15 4420 - 4423 Elsevier 2010年08月 
    Salacinol is a potent α-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 α-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.
  • 村田克美; 永田尚也; 北浦和夫; 仲西 功
    Journal of Computational Chemistry 31 4 791 - 796 Wiley 2010年03月 
    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 thisapproach, 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.
  • 今井友美; 北浦和夫; 仲西 功; 井上佳久
    J. Comput. Chem. 30 14 2267 - 2276 2009年11月 
    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 84 - 89 メディカルドゥ 2009年09月
  • 今井友美; 北浦和夫; 仲西 功; 井上佳久
    QSAR Comb.Sci. 28 8 869 - 873 2009年08月 
    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.
  • 関口雄介; 仲庭哲子; 木下誉富; 多田俊治; 仲西 功; 北浦和夫; 平澤明; 辻本豪三
    Bioorg. Med. Chem. Lett. 19 11 2920 - 2923 Elsevier 2009年06月 
    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年05月
  • Takahiro Kosugi; Isao Nakanishi; Kazuo Kitaura
    JOURNAL OF CHEMICAL INFORMATION AND MODELING 49 3 615 - 622 2009年03月 
    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.
  • 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 65 65 75 - 79 2009年02月 
    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.
  • Katsumi Murata; Dmitri G. Fedorov; Isao Nakanishi; Kazuo Kitaura
    JOURNAL OF PHYSICAL CHEMISTRY B 113 3 809 - 817 2009年01月 
    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.
  • Takayoshi Kinoshita; Toshiji Tada; Isao Nakanishi
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 373 1 53 - 57 2008年08月 
    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.
  • 今井友美; 北浦和夫; 仲西 功; 井上佳久
    Protein Science 17 7 1129 - 1137 Cold Spring Harbor Laboratory Press 2008年07月 
    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.
  • 井上豪; 井上豪; 安達宏昭; 村上聡; 高野和文; 松村浩由; 森勇介; 福西快文; 中村春木; 中村春木; 木下誉富; 仲西功; 奥野恭史; 南方聖司; 下条真司; 下条真司; 坂田恒昭; 坂田恒昭
    薬学雑誌 128 4 497 - 505 公益社団法人日本薬学会 2008年04月 [査読有り]
     
      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.
  • Isao Nakanishi; Dmitri G. Fedorov; Kazuo Kitaura
    PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS 68 1 145 - 158 2007年07月 [査読有り]
     
    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.
  • Nakamura S; Nakanishi I; Kitaura K
    Bioorganic & medicinal chemistry letters 16 24 6334 - 6337 2006年12月 [査読有り]
  • Masako Kuno; Nobuo Seki; Susumu Tsujimoto; Isao Nakanishi; Takayoshi Kinoshita; Katsuya Nakamura; Tadashi Terasaka; Nobuya Nishio; Akihiro Sato; Takashi Fujii
    European Journal of Pharmacology 534 1-3 241 - 249 2006年03月 
    Adenosine has anti-inflammatory activity. Adenosine deaminase (EC 3.5.4.4) metabolizes extracellular adenosine, resulting in an exacerbation of inflammation. Consequently, it was hypothesized that adenosine deaminase inhibitors produce anti-inflammatory activity by increasing extracellular adenosine concentration. This group recently developed a non-nucleoside adenosine deaminase inhibitor, FR234938, by using rational structure-based drug design. FR234938 inhibits recombinant human adenosine deaminase enzyme competitively. FR234938 inhibits interleukin (IL)-6-dependent immunoglobulin (Ig) M production by SKW6.4 cells, in the presence of adenosine. Inhibitory effect of FR234938/adenosine combination is blocked by an A2a adenosine receptor antagonist. FR234938 also inhibits anti-type II collagen delayed type hypersensitivity (DTH) in a dose-dependent manner, both in the presence and absence of recombinant human adenosine deaminase. Moreover, FR234938 inhibits tumor necrosis factor (TNF)-α and IL-10 production in a lipopolysaccharide (LPS)-induced cytokine production model in mice. These results indicate that FR234938 has potential anti-inflammatory activity. Non-nucleoside adenosine deaminase inhibitor FR234938 has good potential as a new type of anti-rheumatic and anti-inflammatory drug, by modulating host-defense concentrations of adenosine. © 2006 Elsevier B.V. All rights reserved.
  • Murata Katsumi; Nagata Naoya; Nakanishi Isao; Kitaura Kazuo
    生物物理 46 2 S400  一般社団法人 日本生物物理学会 2006年
  • 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 44 31 10562 - 10569 2005年08月 
    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.
  • 仲西 功; Fedorov Dmitri; 北浦 和夫
    生物物理 45 S237  一般社団法人 日本生物物理学会 2005年
  • 小杉 貴洋; 仲西 功; 北浦 和夫
    生物物理 45 S42  一般社団法人 日本生物物理学会 2005年
  • Tadashi Terasaka; Takayoshi Kinoshita; Masako Kuno; Isao Nakanishi
    Journal of the American Chemical Society 126 1 34 - 35 2004年01月 
    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.
  • Takayoshi Kinoshita; Isao Nakanishi; Masaichi Warizaya; Akinori Iwashita; Yoshiyuki Kido; Kouji Hattori; Takashi Fujii
    FEBS Letters 556 1-3 43 - 46 2004年01月 
    The crystal structure of human recombinant poly(ADP-ribose) polymerase (PARP) complexed with a potent inhibitor, FR257517, was solved at 3.0 Å resolution. The fluorophenyl part of the inhibitor induces an amazing conformational change in the active site of PARP by motion of the side chain of the amino acid, Arg878, which forms the bottom of the active site. Consequently, a corn-shaped hydrophobic subsite, which consists of the side chains of Leu769, Ile879, Pro881, and the methylene chain of Arg878, newly emerges from the well-known active site. © 2003 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
  • Tadashi Terasaka; Isao Nakanishi; Katsuya Nakamura; Yoshiteru Eikyu; Takayoshi Kinoshita; Nobuya Nishio; Akihiro Sato; Masako Kuno; Nobuo Seki; Kazuo Sakane
    Bioorganic and Medicinal Chemistry Letters 13 22 4147  2003年11月
  • Tadashi Terasaka; Isao Nakanishi; Katsuya Nakamura; Yoshiteru Eikyu; Takayoshi Kinoshita; Nobuya Nishio; Akihiro Sato; Masako Kuno; Nobuo Seki; Kazuo Sakane
    Bioorganic and Medicinal Chemistry Letters 13 6 1115 - 1118 2003年03月 
    We searched for non-nucleoside inhibitors of adenosine deaminase by rational structure-based de novo design and succeeded in the discovery of 1-(1-hydroxy-4-phenyl-2-butyl)imidazole-4-carboxamide (FR221647: Ki=5.9 μM to human ADA) as a novel inhibitor with moderate activity and good pharmacokinetics compared with the known inhibitors pentostatin and EHNA. © 2003 Elsevier Science Ltd. All rights reserved.
  • Takayoshi Kinoshita; Nobuya Nishio; Isao Nakanishi; Akihiro Sato; Takashi Fujii
    Acta Crystallographica - Section D Biological Crystallography 59 2 299 - 303 2003年02月 
    The crystal structure of adenosine deaminase (ADA) from bovine intestine complexed with a transition-state analogue, 6-hydroxy-1,6-dihydropurine riboside (HDPR), was solved at 2.5 Å resolution by the molecular-replacement method using a homology model based on the crystal structure of mouse ADA. The final refinement converged to a crystallographic R factor of 20.7%. The Cα backbone of bovine ADA is mostly superimposable on that of mouse ADA, although mouse ADA itself did not lead to a solution by molecular replacement. HDPR tightly interacts with ADA by means of six hydrogen bonds and is entirely enclosed within the active site. The lid of the envelope consists of two components: one contains two leucine residues, Leu55 and Leu59, and the other contains the backbone atoms Asp182 and Glu183. The Cδ atoms of the two leucine residues are 3.5 Å from the respective N atoms of the backbone. A weak interaction, similar to CH-π binding, might make it possible to open the lid. Taking account of the movement and observation of this structural feature, the aim is to design novel ADA inhibitors.
  • Takayoshi Kinoshita; Isao Nakanishi; Akihiro Sato; Toshiji Tada
    Bioorganic and Medicinal Chemistry Letters 13 1 21 - 24 2003年01月 [査読有り]
     
    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.
  • Isao Nakanishi; Takayoshi Kinoshita; Akihiro Sato; Toshiji Tada
    Biopolymers 53 5 434 - 445 2000年04月 [査読有り]
     
    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.
  • Isao Nakanishi; Takayoshi Kinoshita; Toshiji Tada; Takashi Fujita; Hiroshi Hatanaka; Akihiro Sato
    Bioorganic and Medicinal Chemistry Letters 9 16 2397 - 2402 1999年08月 [査読有り]
     
    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.
  • OHKUBO Mitsuru; KUNO Atsushi; KATSUTA Kiyotaka; UEDA Yoshiko; SHIRAKAWA Kiyoharu; NAKANISHI Hajime; NAKANISHI Isao; KINOSHITA Takayoshi; TAKASUGI Hisashi
    Chemical and Pharmaceutical Bulletin 44 1 95 - 102 公益社団法人 日本薬学会 1996年 
    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.
  • 谷口 清; 奥村 和央; 嶽 一彦; 椿 一典; 寺井 孝雄; 仲西 功; 塩川 洋一
    Chemical and Pharmaceutical Bulletin 43 1 71 - 77 公益社団法人 日本薬学会 1995年 
    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.

MISC

書籍等出版物

  • 大地からの贈り物サラシア
    仲西功 (担当:分担執筆範囲:PP176-185)メディカルレビュー社 2018年
  • くすりをつくる研究者の仕事
    仲西功 (担当:共著範囲:第5章)化学同人 2017年03月
  • わかりやすい物理化学 第2版
    仲西 功 (担当:共著範囲:)廣川書店 2010年09月
  • コンピュータで薬を創ろう
    仲西 功 (担当:共著範囲:)ケイディーネオブック 2009年06月
  • インシリコ創薬化学-ゲノム情報から創薬へ-
    仲西 功 (担当:共著範囲:)京都廣川書店 2008年07月
  • 新しい薬をどう創るか
    仲西功 (担当:共著範囲:第4章)講談社ブルーバックス 2007年04月

講演・口頭発表等

  • 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年12月 ポスター発表
  • 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年12月 ポスター発表
  • 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年12月 ポスター発表
  • 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年11月
  • 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年11月
  • 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  [通常講演]
    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年10月 ポスター発表
  • 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年10月
  • 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―  [通常講演]
    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年10月
  • 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年10月
  • 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  [通常講演]
    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年10月
  • 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  [通常講演]
    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年09月
  • SBDDと計算化学-少ない計算資源で-  [招待講演]
    仲西 功
    第19回FMO研究会 2019年09月 口頭発表(招待・特別)
  • 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年08月
  • 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  [通常講演]
    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年06月 日本疼痛学会
  • 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年
  • 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  [通常講演]
    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年 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  [通常講演]
    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年 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  [通常講演]
    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年 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  [通常講演]
    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年 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  [通常講演]
    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年 姫路
  • 3Dプリンタを用いた医薬品分子模型の作成  [通常講演]
    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年 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  [通常講演]
    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年 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  [通常講演]
    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年 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  [通常講演]
    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年 広島
  • SDO-VS法の精度向上研究:擬似分子の構成要素の検討  [通常講演]
    中村 真也; 北吉 駿; 仲西 功
    日本薬学会第138年会 2018年 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  [通常講演]
    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年 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  [通常講演]
    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年 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  [通常講演]
    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年 金沢
  • HPCを活用した医薬品設計研究  [通常講演]
    仲西 功
    第1回近畿大学生物理工学部HPCシンポジウム 2018年 和歌山
  • 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年
  • ATP 部位及びアロステリック部位に結合するCK2α1 阻害剤  [通常講演]
    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年 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  [通常講演]
    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年 神戸
  • CK 2a1-hemateinの結合を変化させる間接的要因  [通常講演]
    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年 仙台
  • Hydroxychavicol をシードとした XO 阻害化合物の探索研究  [通常講演]
    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年 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  [通常講演]
    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年 仙台
  • Crystal structure of CK2α2 in the new crystal form. 8th International Conference on Protein Kinase CK2  [通常講演]
    Masato Tsuyuguchi; Tetsuko Nakaniwa; Isao Nakanishi; Takayoshi Kinoshita
    8th International Conference on Protein Kinase CK2 2016年 Homburg (Germany)
  • Homology modeling of CCR4 and its evaluation based on the structure-activity relationship  [通常講演]
    Keiji Nishiwaki; Masashi Fujimoto; Shinya Nakamura; Isao Nakanishi
    21st EuroQSAR 2016年 Verona (Italy)
  • Evaluation of predicted binding structures of virtual screening hit compounds.  [通常講演]
    Isao Nakanishi; Yusuke Namba; Shinya Nakamura; Takayoshi Kinoshita
    21st EuroQSAR 2016年 Verona (Italy)
  • Different binding modes of apigenin in homologous proteins, human CK2α and maize CK2α.  [通常講演]
    Shinya Nakamura; Atsushi Sakurai; Takayoshi Kinoshita; Isao Nakanishi
    21st EuroQSAR 2016年 Verona (Italy)
  • Solvent Dipole Orderingの創薬への応用研究  [通常講演]
    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年 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  [通常講演]
    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年 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  [通常講演]
    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年 横浜
  • CK2サブタイプ間で異なるhemateinの相互作用様式の解明  [通常講演]
    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年 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  [通常講演]
    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年 大阪
  • CK2 α2の高分解能X線結晶構造解析  [通常講演]
    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年 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  [通常講演]
    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 大阪
  • Structural basis for producing CK2α1-specific inhibitors: Crystal structures of hematein with CK2α1 and CK2α2  [通常講演]
    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年 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  [通常講演]
    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年 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  [通常講演]
    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年 神戸
  • Binding pose prediction of Xantine oxidase inhibitor hydroxychavicol and drug design of its analogues.  [通常講演]
    International Symposium on Medicinal Chemistry 2014 2014年 Lisbon International Symposium on Medicinal Chemistry 2014
  • Identification of protein kinase CK2 inhibitors by the solvent ordering virtual screening method.  [通常講演]
    International Symposium on Medicinal Chemistry 2014 2014年 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.  [通常講演]
    International Symposium on Medicinal Chemistry 2014 2014年 Lisbon International Symposium on Medicinal Chemistry 2014
  • Species-dependent variation in the structure of CK2a-apigenin complex.  [通常講演]
    23rd Congress and General Assembly of the International Union of Crystallography 2014年 Montreal 23rd Congress and General Assembly of the International Union of Crystallography
  • Binding mode analysis of protein kinase CK2 inhibitors with a purine scaffold.  [通常講演]
    CBI Annual Meeting 2014 2014年 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  [通常講演]
    仲西 功
    第356回CBI学会研究講演会 2014年 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  [通常講演]
    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年 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  [通常講演]
    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年 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  [通常講演]
    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年 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  [通常講演]
    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年 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  [通常講演]
    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年 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  [通常講演]
    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年 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  [通常講演]
    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年 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  [通常講演]
    中村 真也; 大村 梨恵; 仲西 功
    日本薬学会第134年会 2014年 熊本
  • Crystal structure of human CK2α at 1.04 ? resolution.  [通常講演]
    Takayoshi Kinoshita; Tetsuko Nakaniwa; Yusuke Sekiguchi; Yuri Sogabe; Atsushi Sakurai; Isao Nakanishi
    2013年 Nagoya
  • Structural insight into human CK2α with a flavonoid inhibitor.  [通常講演]
    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年 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  [通常講演]
    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年 熊本
  • 連続縮環型分子の修飾による KSP 阻害剤の溶解性  [通常講演]
    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年 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  [通常講演]
    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年 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  [通常講演]
    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年 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  [通常講演]
    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年 兵庫
  • SDOVS: A Solvent Dipole Ordering-based Method for Virtual Screening  [通常講演]
    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年 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  [通常講演]
    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年 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  [通常講演]
    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年 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  [通常講演]
    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年 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  [通常講演]
    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年 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―  [通常講演]
    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年 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  [通常講演]
    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年 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  [通常講演]
    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年 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  [通常講演]
    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年 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  [通常講演]
    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年11月 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  [通常講演]
    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年11月 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  [通常講演]
    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年11月 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  [通常講演]
    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年11月 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  [通常講演]
    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年10月 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  [通常講演]
    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年10月 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  [通常講演]
    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年10月 京都
  • Binding energy estimation of CK2 inhibitors by the ab initio-based fragment molecular orbital method.  [通常講演]
    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年09月 Berlin
  • SDOVS: A solvent dipole ordering-based method for virtual screening.  [通常講演]
    Naoya Nagata; Katsumi Murata; Isao Nakanishi; Kazuo Kitaura
    2012年09月 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  [通常講演]
    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年08月 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  [通常講演]
    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年08月 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  [通常講演]
    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年05月 大阪
  • LynおよびLckキナーゼの阻害剤との相互作用解析  [通常講演]
    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年11月 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  [通常講演]
    中尾 佳人; 中村 真也; 仲西 功
    第34回情報化学討論会 2011年11月 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  [通常講演]
    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年11月 長崎
  • α-Glucosidase阻害剤salacinolの3’位疎水化の活性に及ぼす効果  [通常講演]
    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年10月 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  [通常講演]
    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年09月 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  [通常講演]
    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年03月 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  [通常講演]
    呉 竜英; 中村 真也; 仲西 功
    日本薬学会第132年会 2011年03月 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  [通常講演]
    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年03月 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  [通常講演]
    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年03月 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  [通常講演]
    中尾 佳人; 中村 真也; 仲西 功
    日本薬学会第131年会 2011年03月 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  [通常講演]
    高平 和典; 中村 真也; 村岡 修; 仲西 功
    日本薬学会第131年会 2011年03月 静岡 日本薬学会
  • CK2阻害剤Hemateinの結合様式の予測  [通常講演]
    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年03月 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  [通常講演]
    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年10月 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.  [通常講演]
    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年09月 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  [通常講演]
    仲西 功
    第3回サラシア属植物シンポジウム 2010年08月 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  [通常講演]
    中村 真也; 仲西 功
    MOEフォーラム2010 2010年07月 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  [通常講演]
    仲西 功
    構造活性フォーラム2010 2010年06月 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  [通常講演]
    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年03月 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  [通常講演]
    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年03月 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  [通常講演]
    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年11月 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  [通常講演]
    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年10月 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  [通常講演]
    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年10月 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.  [通常講演]
    木下誉富; 多田俊治; 仲西 功
    25th European Crystallographic Meeting 2009年08月 Istanbul (Turkey) 25th European Crystallographic Meeting
  • An approach for producing a CK2alpha inhibitor using X-ray, calculation and ITC.  [通常講演]
    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年08月 Istanbul (Turkey) 25th European Crystallographic Meeting
  • サラシア属植物有効成分のin silico解析  [通常講演]
    仲西 功
    第2回サラシア属植物シンポジウム 2009年08月 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  [通常講演]
    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年05月 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  [通常講演]
    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年05月 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  [通常講演]
    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年03月 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  [通常講演]
    浅田直也; 北浦和夫; 仲西 功
    日本薬学会第129年会 2009年03月 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  [通常講演]
    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年03月 京都 日本薬学会第129年会
  • フラグメントMO法による構造最適化に対する電子相関の影響  [通常講演]
    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年03月 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.  [通常講演]
    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年11月 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.  [通常講演]
    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年11月 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  [通常講演]
    中村 真也; 仲西 功; 北浦 和夫
    8th China-Japan symposium on drug design and development 2008年10月 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.  [通常講演]
    浅田直也; 北浦和夫; 仲西 功
    European QSAR symposium 2008 2008年09月 Uppsara (Sweden) European QSAR symposium 2008
  • Cl?π interactions in protein?ligand complexes.  [通常講演]
    今井友美; 北浦和夫; 仲西 功; 井上佳久
    European QSAR symposium 2008 2008年09月 Uppsara (Sweden) European QSAR symposium 2008
  • Crystal structure of human CK2 alpha in complex with ellagic acid.  [通常講演]
    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年08月 大阪 IUCr2008
  • Quantum chemical calculation of protein-ligand interaction.  [通常講演]
    仲西 功
    XXth EFMC-ISMC 2008年08月 Vienna (Austria) XXth EFMC-ISMC
  • Structure of the catalytic subunit of human protein kinase CK2alpha prime with a potent inhibitor.  [通常講演]
    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年08月 大阪 IUCr2008

所属学協会

  • 日本ケミカルバイオロジー学会   情報計算化学生物学会   日本薬学会   

共同研究・競争的資金等の研究課題

  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2015年04月 -2018年03月 
    代表者 : 藤井 信孝; 大野 浩章; 仲西 功; 大石 真也
     
    環状ペンタペプチド構造からなるCXCR7受容体リガンドの構造活性相関研究を展開し、生物活性に必要なアミノ酸残基を同定するとともに、複数の高活性かつ選択的なリガンドを見出した。分子モデリングによる相互作用解析を行い、受容体結合に寄与する複数の相互作用を明らかにした。また、創薬研究を加速する複素環骨格構築法の検討を行い、天然物にみられる複数の含窒素複素環骨格の効率的な合成プロセスを開発した。さらに、スフィンゴシンキナーゼ、CK2、NK3受容体に対する創薬研究を行い、ユニークな特性を有するさまざまな阻害剤を同定するとともに、生物活性等に寄与する修飾基の役割を明らかにした。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2010年 -2012年 
    代表者 : 仲西 功; 北浦 和夫
     
    Free energy perturbation (FEP)法・Thermodynamic integration (TI)法を用い、既知リガンドの極微小な構造変化による高活性リガンドを探索する手法の検討を行なった。種々の条件検討を行ないながら本法をタンパク質-リガンド複合体系に適用した結果、Protein kinase CK2のリガンドの活性変化を精度よく再現することに成功した。また、合成可能な化合物の網羅的なアフィニティ予測により、既知リガンドの活性を上回る可能性のあるリガンドの候補を見出した。最適化された計算法は、再現性も良好であり、創薬の現場でも活用できるレベルのものであると考えられる。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2008年 -2010年 
    代表者 : 北浦 和夫; 仲西 功
     
    フラグメント分子軌道(FMO)法と有効フラグメントポテンシャル(EFP)法や古典力場(MM)との融合法、さらに溶媒の連続誘電体モデル(PCM)とを融合したマルチレベル統合FMO 法を開発した。この方法により、水溶液中のタンパク質やタンパク質-リガンド複合体の高速な計算が可能になり、生体高分子のシミュレーション研究に貢献するすることが期待される。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2006年 -2008年 
    代表者 : 仲西 功; 北浦 和夫
     
    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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