KINDAI UNIVERSITY


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KAWASHITA Norihito

Profile

FacultyDepartment of Life Science / Graduate School of Science and Engineering Research
PositionLecturer
DegreePh. D. in Pharmaceutical Sciences
Commentator Guidehttps://www.kindai.ac.jp/meikan/2112-kawashita-norihito.html
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Last Updated :2020/09/30

Education and Career

Academic & Professional Experience

  •   2008 , - Assistant Professor, Research Institute for Microbial Diseases, Osaka University

Research Activities

Research Areas

  • Life sciences, Virology
  • Life sciences, Pharmaceuticals - chemistry and drug development
  • Life sciences, Pharmaceuticals - analytical and physicochemistry
  • Life sciences, Pharmaceuticals - chemistry and drug development

Research Interests

  • computational chemistry, molecular design, antiviral agent, infection

Published Papers

  • Genetic and genomic basis of the mismatch repair system involved in Lynch syndrome, Tamura K, Kaneda M, Futagawa M, Takeshita M, Kim S, Nakama M, Kawashita N, Tatsumi-Miyajima J, Int J Clin Oncol., Int J Clin Oncol., 24(9), 999 - 1011, Sep. 2019 , Refereed
  • PB2 mutations arising during H9N2 influenza evolution in the Middle East confer enhanced replication and growth in mammals., Arai Y, Kawashita N, Ibrahim MS, Elgendy EM, Daidoji T, Ono T, Takagi T, Nakaya T, Matsumoto K, Watanabe Y, PLoS Pathog, PLoS Pathog, 15(7), e1007919, Jul. 2019 , Refereed
  • Three-Dimensional Classification Structure-Activity Relationship Analysis Using Convolutional Neural Network., Moriwaki H, Tian YS, Kawashita N, Takagi T, Chem Pharm Bull, Chem Pharm Bull, 67(5), 426 - 432, May 2019 , Refereed
  • Multiple polymerase gene mutations for human adaptation occurring in Asian H5N1 influenza virus clinical isolates., Arai Y, Kawashita N, Hotta K, Hoang PVM, Nguyen HLK, Nguyen TC, Vuong CD, Le TT, Le MTQ, Soda K, Ibrahim MS, Daidoji T, Takagi T, Shioda T, Nakaya T, Ito T, Hasebe F, Watanabe Y, Scientific reports, Scientific reports, 8(1), 13066, Aug. 2018 , Refereed
  • Mordred: a molecular descriptor calculator, Hirotomo Moriwaki, Yu-Shi Tian, Norihito Kawashita, Tatsuya Takagi, J. Cheminformatics, J. Cheminformatics, 10(4), 4, Feb. 2018 , Refereed
  • Novel Concepts for Drug Hypersensitivity Based on the Use of Long-Time Scale Molecular Dynamic Simulation, Murai Takahiro, Kawashita Norihito, Tian Yu-Shi, Takagi Tatsuya, JOURNAL OF PHARMACEUTICS, JOURNAL OF PHARMACEUTICS, 2016, 9520361, 2016 , Refereed
  • > A Mini-review on Chemoinformatics Approaches for Drug Discover, KAWASHITA Norihito, KAWASHITA Norihito, YAMASAKI Hiroyuki, MIYAO Tomoyuki, KAWAI Kentaro, SAKAE Yoshitake, ISHIKAWA Takeshi, MORI Kenichi, NAKAMURA Shinya, KANEKO Hiromasa, J Comput Aided Chem (Web), J Comput Aided Chem (Web), 16, 15-29 (J-STAGE), 2015
  • Erratum: Anionic polymer, poly(methyl vinyl ether-maleic anhydride)-coated beads-based capture of human influenza A and B virus (Bioorg. Med. Chem. (2009) 17 (752-757)), Akikazu Sakudo, Koichi Baba, Megumi Tsukamoto, Atsuko Sugimoto, Takashi Okada, Takanori Kobayashi, Norihito Kawashita, Tatsuya Takagi, Kazuyoshi Ikuta, Bioorganic and Medicinal Chemistry, Bioorganic and Medicinal Chemistry, 19, 1010, Jan. 15 2011
  • Recent Advances in the Development of Small-Molecule Compounds Targeting HIV-1 gp41 as Membrane Fusion Inhibitors, Mini-Reviews in Organic Chemistry, Mini-Reviews in Organic Chemistry, in press, 2011
  • Design and evaluation of antiretroviral peptides corresponding to the C-terminal heptad repeat region (C-HR) of human immunodeficiency virus type 1 envelope glycoprotein gp41, Bongkot Soonthornsata, Yu-Shi Tian, Piraporn Utachee, Sompong Sapsutthipas, Panasda Isarangkura-na-ayuthaya, Wattana Auwanit, Tatsuya Takagi, Kazuyoshi Ikuta, Pathom Sawanpanyalert, Norihito Kawashita, Masanori Kameoka, Virology, Virology, 405(1), 157-164, Sep. 2010 , Refereed
    Summary:Two alpha-helical heptad repeats, N-HR and C-HR, located in the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp41, play an important role in membrane fusion by forming a 6-helix bundle. C34, a peptide mimicking C-HR, inhibits the formation of the 6-helix bundle; thus, it has potential as a novel antiretroviral compound. In order to improve the inhibitory effect of C34 on HIV-1 replication, we designed new C34-derived peptides based on computational analysis of the stable conformation of the 6-helix bundle. Newly designed peptides showed a stronger inhibitory effect on the replication of recombinant viruses containing CRF01_AE, subtype B or subtype C Env than C34 or a fusion inhibitor, T-20. In addition, these peptides inhibited the replication of a T-20-resistant virus. We propose that these peptides could be applied to develop novel antiretroviral compounds to inhibit the replication of various subtypes of HIV-1 as well as of T-20-resistant variants.
  • Nonlinear classification of drug-induced arrhythmogenic activity by unsupervised classification method, Shinnosuke HIDAKA, Hiroyuki YAMASAKI, Yoshihiro OHMAYU, Akiko MATSUURA, Kousuke OKAMOTO, Norihito KAWASHITA, Tatsuya TAKAGI, The Journal of Toxicological Sciences, The Journal of Toxicological Sciences, in press, May 2010 , Refereed
    Summary:The side effects that occur in the central nervous system and circulatory system due to medicines are expected to be prevented by research and development. However, many of the compounds in medicines have the possibility of causing arrhythmia, and methods developed to detect this problem at the early stage of drug development are not always successful. In the present study, we classified drug compounds according to their activity using only structural information. To classify compounds, we used a self-organizing map (SOM), which is a nonlinear unsupervised classification method. We first analyzed a small-scale dataset, and an excellent classification result was obtained. We then applied our method to a large-scale dataset containing numerous inert compounds and were again able to classify the compounds according to their activity. Both classifications showed some compound activity, although a few differences between the two SOM maps were seen.
  • Ecotoxicity Prediction Using 3D Descriptors, Shinnosuke Hidaka, Hiroaki Shiraishi, Yoshihiro Ohmayu, Hiroyuki Yamasaki, Kousuke Okamoto, Norihito Kawashita, Teruo Yasunaga, Tatsuya Takagi, Journal of Computer Aided Chemistry, Journal of Computer Aided Chemistry, vol.11, 11-18, Feb. 2010 , Refereed
    Summary:A vast quantity of chemicals are present in our environment and are considered indispensable to our high technological society. However, there are some chemicals that are hazardous and that can extensively impact both human health and the global environment. In Japan, ecotoxicity tests of chemical substances have been conducted with the goal of contributing to the Organization for Economic Cooperation and Development (OECD) evaluation program for harmful high-production volume (HPV) chemicals since 1995. To date, only about 500 compounds have been tested. There is a possibility that quantitative structure-activity relationships (QSARs) may enable us to predict environmental toxicities and fates as well as the physical and chemical properties of compounds; therefore, the toxicity prediction by QSARs is a possible alternative to the measurements of their ecotoxicities. In this study, we generated QSAR models from toxicity tests of Daphnids using only 3D descriptors to examine the availability of particular 3D descriptors for predicting of the ecotoxicity of compounds with various structures. Predicton accuracy of the model generated in this study was adequate and improved compared to
  • Signal Detection of Drug Complications Applying Association Rule Learning for Stevens-Johnson Syndrome, Yuko Shirakuni, Kousuke Okamoto, Norihito Kawashita, Teruo Yasunaga, Tatsuya Takagi, Journal of Computer Aided Chemistry, Journal of Computer Aided Chemistry, 10, 118-127, Nov. 2009 , Refereed
    Summary:The adverse events induced by drugs have been complicated, when two or more drugs are administrated for a patient. We selected "Stevens-Johnson Syndrome (SJS) " as a research object, which is one of the severe skin manifestations. The data source is a database constructed by the Food and Drug Administration (FDA). FDA's post-marketing safety surveillance program is supported by the Adverse Event Reporting System (AERS). AERS is designed with a computerized information database. To analyze the relationships between the concurrent medication and SJS in this study, we applied association rule learning. Our purpose is to propose an efficient procedure that enables the detection of signals for drugs related to an adverse event, without assuming the involvement of a specific drug. We defined new value K for the evaluation of existing signal detection. Association rule was evaluated according to criterion K value. As a result, it was suggested to obtain a strong signal by combining two concomitant drugs. Association rule learning in this study was applicable for the analysis of the relationships between adverse events and pairs of drugs.
  • Computational Studies of gp41 6-Helix Bundle: Do Stabilized Energy of HIV Membrane Fusion Inhibitor C34 and Interaction Energy of gp41 6-Helix Bundle have Good Correlation with their Inhibitory Activity?, Kawashita N, Tian Y.-S, Yasuda M, de Silva U. C, Kashiwada R, Nakamura S, Goto N, Nishikiori R, Okamoto K, Kameoka M, Yasunaga T, Kawase M, Ikuta K, Takagi T, Antiviral Research, Antiviral Research, 78(2), A42, (2008), Apr. 2008 , Refereed
  • Development of Fingerprint Verification Type Self-Organized Map Applied to Profiling Seized Methamphetamine., Rika Nishikiori, Yukiko Makino, Yukino Ochi, Noriyuki Yamashita, Kousuke Okamoto, Norihito Kawashita, Jun-ichi Takahara, Teruo Yasunaga, Tatsuya Takagi, Masaya Kawase, J. Comput. Aided Chem., J. Comput. Aided Chem., 9, 30-36, Mar. 2008 , Refereed
  • Regioselective, nucleophilic carbon-carbon bond formation at the C4-position of indoles initiated by the aromatic Pummerer-type reaction, S Akai, N Kawashita, Y Wada, H Satoh, AH Alinejad, K Kakiguchi, Kuriwaki, I, Y Kita, TETRAHEDRON LETTERS, TETRAHEDRON LETTERS, 47(12), 1881 - 1884, Mar. 2006 , Refereed
    Summary:The treatment of the 5-(phenylsulfinyl) in doles with trifluoroacetic anhydride in the presence of carbon nucleophiles achieved the title reactions with complete regioselectivity. (c) 2006 Elsevier Ltd. All rights reserved.
  • Metal-Free Nitrogen-Containing Polyheterocyclic Near-Infrared (NIR) Absorption Dyes: Synthesis, Absorption Properties, and Theoretical Calculation of Substituted 5-Methylisoindolo[2,1- a]quinolines, Yuki Fujii, Yukinori Suwa, Yuki Wada, Tsunayoshi Takehara, Takeyuki Suzuki, Yusuke Kawashima, Norihito Kawashita, Tatsuya Takagi, Hiromichi Fujioka, Mitsuhiro Arisawa, ACS Omega, ACS Omega, 4(3), 5064 - 5075, Mar. 08 2019 , Refereed
    Summary:© 2019 American Chemical Society. We have synthesized and theoretically calculated 5-methylisoindolo[2,1-a]quinoline derivatives as novel near-infrared absorption dyes via a ruthenium-catalyzed one-pot metathesis/oxidation/1,3-dipolar cycloaddition protocol. The reactivity in 1,3-dipolar cycloaddition was governed by the electronic effect of aromatic ring substituents. Substrates with an electron-withdrawing group on the aromatic ring afforded higher yields. The maximal absorption wavelength of 3,5-dimethyl-11-phenylisoindolo[2,1-a]quinoline-7,10-dione and 11-(4-methoxyphenyl)-5-methylisoindolo[2,1-a]quinoline-7,10-dione in MeOH increased to 736 and 737 nm, although that of 3a was 727 nm.
  • Characterization of H5N1 influenza virus quasispecies with adaptive hemagglutinin mutations from single-virus infections of human airway cells, Yohei Watanabe, Yasuha Arai, Norihito Kawashita, Madiha S. Ibrahim, Emad M. Elgendy, Tomo Daidoji, Junichi Kajikawa, Hiroaki Hiramatsu, Nongluk Sriwilaijaroen, Takao Ono, Tatsuya Takagi, Kazuo Takahashi, Tatsuo Shioda, Kazuhiko Matsumoto, Yasuo Suzuki, Takaaki Nakaya, Journal of Virology, Journal of Virology, 92(11), Jun. 01 2018 , Refereed
    Summary:Transmission of avian influenza (AI) viruses to mammals involves phylogenetic bottlenecks that select small numbers of variants for transmission to new host species. However, little is known about the AI virus quasispecies diversity that produces variants for virus adaptation to humans. Here, we analyzed the hemagglutinin (HA) genetic diversity produced during AI H5N1 single-virus infection of primary human airway cells and characterized the phenotypes of these variants. During single-virus infection, HA variants emerged with increased fitness to infect human cells. These variants generally had decreased HA thermostability, an indicator of decreased transmissibility, that appeared to compensate for their increase in α2,6- linked sialic acid (α2,6 Sia) binding specificity and/or in the membrane fusion pH threshold, each of which is an advantageous mutational change for viral infection of human airway epithelia. An HA variant with increased HA thermostability also emerged but could not outcompete variants with less HA thermostability. These results provided data on HA quasispecies diversity in human airway cells.
  • Dengue virus and its inhibitors: A brief review, Yu-Shi Tian, Yi Zhou, Tatsuya Takagi, Masanori Kameoka, Norihito Kawashita, Chemical and Pharmaceutical Bulletin, Chemical and Pharmaceutical Bulletin, 66(3), 191 - 206, 2018 , Refereed
    Summary:The global occurrence of viral infectious diseases poses a significant threat to human health. Dengue virus (DENV) infection is one of the most noteworthy of these infections. According to a WHO survey, approximately 400 million people are infected annually symptoms deteriorate in approximately one percent of cases. Numerous foundational and clinical investigations on viral epidemiology, structure and function analysis, infection source and route, therapeutic targets, vaccines, and therapeutic drugs have been conducted by both academic and industrial researchers. At present, CYD-TDV or Dengvaxia® is the only approved vaccine, but potent inhibitors are currently under development. In this review, an overview of the viral life circle and the history of DENVs is presented, and the most recently reported antiviral candidates and newly discovered promising targets are focused and summarized. We believe that these successes and failures have enabled progress in anti-DENV drug discovery and hope that our review will stimulate further innovation in this area.
  • Isolation and characterization of a stress-responsive gene encoding a CHRD domain-containing protein from a halotolerant green alga, Ryo Ishinishi, Hideyuki Matsuura, Satoshi Tanaka, Saaya Nozawa, Keisuke Tanada, Norihito Kawashita, Kazuhito Fujiyama, Hitoshi Miyasaka, Kazumasa Hirata, GENE, GENE, 640, 14 - 20, Jan. 2018 , Refereed
    Summary:The genetic basis of stress resistance in extremophilic microalgae is not well studied. In this study, a gene of unknown function, the cluster58 or CL58 gene, was identified from the halotolerant green alga Chlamydomonas W80 and characterized. The CL58 gene encodes a protein containing a domain of unknown function, the CHRD domain, and a putative secretory signaling sequence at its N-terminus. The levels of CL58 mRNA increased in response to high copper levels and low temperatures. When the CL58 gene was heterologously expressed as a fusion gene with the NanoLuc luciferase gene in Chlamydomonas reinhardtii, a majority of the NanoLuc activity was detected in the culture medium compared with that in the intracellular fraction. A mutagenic analysis revealed that the putative secretory signaling sequence was sufficient for the secretion of the CL58-NanoLuc fusion protein. In addition, we expressed the protein encoded by the CL58 gene in Escherichia coli; the recombinant, soluble protein was then purified. In summary, we identified a novel gene from C. W80 that appears to encode a stress-responsive, CHRD domain-containing secreted protein.
  • Identification of claudin-4 binder that attenuates tight junction barrier function by TR-FRET-based screening assay, Akihiro Watari, Miki Kodaka, Koji Matsuhisa, Yuta Sakamoto, Kota Hisaie, Norihito Kawashita, Tatsuya Takagi, Yoshiaki Yamagishi, Hidehiko Suzuki, Hirofumi Tsujino, Kiyohito Yagi, Masuo Kondoh, SCIENTIFIC REPORTS, SCIENTIFIC REPORTS, 7(1), 14514, Nov. 2017 , Refereed
    Summary:Claudins are key functional and structural components of tight junctions (TJs) in epithelial cell sheets. The C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) binds to claudin-4 and reversibly modulates intestinal TJ seals, thereby enhancing paracellular transport of solutes. However, the use of C-CPE as an absorption enhancer is limited by the molecule's immunogenicity and manufacturing cost. Here, we developed a high-throughput screening system based on the Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) method to identify claudin-4 binders in a library collection of 32,560 compounds. Thiostrepton, identified from the screen, decreased transepithelial electrical resistance and increased flux of 4-kDa fluorescein isothiocyanate-labelled dextran (FD-4) in Caco-2 cell monolayers, a model of intestinal epithelium. Thiostrepton changed the expression, but not the localisation, of TJ components. Treatment of rat jejunum with thiostrepton increased the absorption of FD-4 without tissue toxicity, indicating that thiostrepton is a novel claudin-4 binder that enhances intestinal permeability. The screening system may therefore be a useful tool for identifying claudin-4 binders to enhance drug absorption in mucosa.
  • Identification of polymerase gene mutations that affect viral replication in H5N1 influenza viruses isolated from pigeons, Emad Mohamed Elgendy, Yasuha Arai, Norihito Kawashita, Tomo Daidoji, Tatsuya Takagi, Madiha Salah Ibrahim, Takaaki Nakaya, Yohei Watanabe, JOURNAL OF GENERAL VIROLOGY, JOURNAL OF GENERAL VIROLOGY, 98(1), 6 - 17, Jan. 2017 , Refereed
    Summary:Highly pathogenic avian influenza virus H5N1 infects a wide range of host species, with a few cases of sporadic pigeon infections reported in the Middle East and Asia. However, the role of pigeons in the ecology and evolution of H5N1 viruses remains unclear. We previously reported two H5N1 virus strains, isolated from naturally infected pigeons in Egypt, that have several unique mutations in their viral polymerase genes. Here, we investigated the effect of these mutations on H5N1 polymerase activity and viral growth and identified three mutations that affected viral polymerase activity. The results showed that the PB1-V3D mutation significantly decreased polymerase activity and viral growth in both mammalian and avian cells. In contrast, the PB2-K627E and PA-K158R mutations had moderate effects: PB2-K627E decreased and PAK158R increased polymerase activity. Structural homology modelling indicated that the PB1-V3D residue was located in the PB1 core region that interacts with PA, predicting that the PB1 mutation would produce a stronger interaction between PB1 and PA that results in decreased replication of pigeon-derived H5N1 viruses. Our results identified several unique mutations responsible for changes in polymerase activity in H5N1 virus strains isolated from infected pigeons, emphasizing the importance of avian influenza surveillance in pigeons and in studying the possible role of pigeon-derived H5N1 viruses in avian influenza virus evolution.
  • In silico analysis of enantioselective binding of immunomodulatory imide drugs to cereblon, Takahiro Murai, Norihito Kawashita, Yu-Shi Tian, Tatsuya Takagi, SPRINGERPLUS, SPRINGERPLUS, 5(1), 1122, Jul. 2016 , Refereed
    Summary:Background: Thalidomide and its analogs, lenalidomide and pomalidomide (referred to as immunomodulatory imide drugs or IMiDs) have been known to treat multiple myeloma and other hematologic malignancies as well as to cause teratogenicity. Recently the protein cereblon was identified as the primary target of IMiDs, and crystallographic studies of the cereblon-IMiDs complex showed strong enantioselective binding for the (S)-enantiomer of IMiDs. Results: Using the structures of cereblon and IMiDs [both (S)-enantiomers and (R)-enantiomers] we performed docking simulations in order to replicate this enantiomeric selectivity and to identify the region(s) contributing to this selectivity. We confirmed the enantioselective binding of IMiDs to cereblon with high accuracy, and propose that the hairpin connecting the beta 10-beta 11 region of cereblon (residues 351-355) contributes to this selectivity and to the increased affinity with IMiDs. Conclusions: Our docking results provide novel insights into the binding mode of IMiD-like molecules and contribute to a deeper understanding of cereblon-related biology.
  • Novel Polymerase Gene Mutations for Human Adaptation in Clinical Isolates of Avian H5N1 Influenza Viruses, Yasuha Arai, Norihito Kawashita, Tomo Daidoji, Madiha S. Ibrahim, Emad M. El-Gendy, Tatsuya Takagi, Kazuo Takahashi, Yasuo Suzuki, Kazuyoshi Ikuta, Takaaki Nakaya, Tatsuo Shioda, Yohei Watanabe, PLOS PATHOGENS, PLOS PATHOGENS, 12(4), e1005583, Apr. 2016 , Refereed
    Summary:A major determinant in the change of the avian influenza virus host range to humans is the E627K substitution in the PB2 polymerase protein. However, the polymerase activity of avian influenza viruses with a single PB2-E627K mutation is still lower than that of seasonal human influenza viruses, implying that avian viruses require polymerase mutations in addition to PB2-627K for human adaptation. Here, we used a database search of H5N1 clade 2.2.1 virus sequences with the PB2-627K mutation to identify other polymerase adaptation mutations that have been selected in infected patients. Several of the mutations identified acted cooperatively with PB2-627K to increase viral growth in human airway epithelial cells and mouse lungs. These mutations were in multiple domains of the polymerase complex other than the PB2-627 domain, highlighting a complicated avian-to-human adaptation pathway of avian influenza viruses. Thus, H5N1 viruses could rapidly acquire multiple polymerase mutations that function cooperatively with PB2-627K in infected patients for optimal human adaptation.
  • Characterization of two anti-dengue human monoclonal antibodies prepared from PBMCs of patients with dengue illness in Thailand, Z. -Y. Li, A. Yamashita, N. Kawashita, T. Sasaki, Y. Pan, K. -I. Ono, K. Ikuta, Y. -G. Li, ACTA VIROLOGICA, ACTA VIROLOGICA, 60(2), 166 - 173, 2016
    Summary:The global spread of the four dengue virus (DENV) serotypes (dengue-1 to -4) has made this virus a major and growing public health concern. Generally, pre-existing neutralizing antibodies derived from primary infection play a significant role in protecting against subsequent infection with the same serotype. By contrast, these pre-existing antibodies are believed to mediate a non-protective response to subsequent heterotypic DENV infections, leading to the onset of dengue illness. In this study, two monoclonal antibodies prepared by using peripheral blood mononuclear cells (PBMCs) from patients with dengue fever were characterized. Epitope mapping revealed that amino acid residues 254-278 in domain II of the viral envelope protein E were the target region of these antibodies. A database search revealed that certain sequences in this epitope region showed high conservation among the four serotypes of DENV. These two human monoclonal antibodies could neutralize DENV-2,-4 more effectively than DENV-1,-3. The amino acid sequences could not explain this difference in neutralizing activity. However, the 3D structure results showed that amino acid 274 could be the critical residue for the difference in neutralization. These results may provide basic information for the development of a dengue vaccine.
  • Characterization of H5N1 influenza virus variants with hemagglutinin mutations isolated from patients, Yohei Watanabe, Yasuha Arai, Tomo Daidoji, Norihito Kawashita, Madiha S. Ibrahim, Emad El-Din M. El-Gendy, Hiroaki Hiramatsu, Ritsuko Kubota-Koketsu, Tatsuya Takagi, Takeomi Murata, Kazuo Takahashi, Yoshinobu Okuno, Takaaki Nakaya, Yasuo Suzuki, Kazuyoshi Ikuta, mBio, mBio, 6(2), Apr. 07 2015
    Summary:A change in viral hemagglutinin (HA) receptor binding specificity from α 2,3- to α 2,6-linked sialic acid is necessary for highly pathogenic avian influenza (AI) virus subtype H5N1 to become pandemic. However, details of the human-adaptive change in the H5N1 virus remain unknown. Our database search of H5N1 clade 2.2.1 viruses circulating in Egypt identified multiple HA mutations that had been selected in infected patients. Using reverse genetics, we found that increases in both human receptor specificity and the HA pH threshold for membrane fusion were necessary to facilitate replication of the virus variants in human airway epithelia. Furthermore, variants with enhanced replication in human cells had decreased HA stability, apparently to compensate for the changes in viral receptor specificity and membrane fusion activity. Our findings showed that H5N1 viruses could rapidly adapt to growth in the human airway microenvironment by altering their HA properties in infected patients and provided new insights into the human-adaptive mechanisms of AI viruses. IMPORTANCE Circulation between bird and human hosts may allow H5N1 viruses to acquire amino acid changes that increase fitness for human infections. However, human-adaptive changes in H5N1 viruses have not been adequately investigated. In this study, we found that multiple HA mutations were actually selected in H5N1-infected patients and that H5N1 variants with some of these HA mutations had increased human-type receptor specificity and increased HA membrane fusion activity, both of which are advantageous for viral replication in human airway epithelia. Furthermore, HA mutants selected during viral replication in patients were likely to have less HA stability, apparently as a compensatory mechanism. These results begin to clarify the picture of the H5N1 human-adaptive mechanism. IMPORTANCE Circulation between bird and human hosts may allow H5N1 viruses to acquire amino acid changes that increase fitness for human infections. However, human-adaptive changes in H5N1 viruses have not been adequately investigated. In this study, we found that multiple HA mutations were actually selected in H5N1-infected patients and that H5N1 variants with some of these HA mutations had increased human-type receptor specificity and increased HA membrane fusion activity, both of which are advantageous for viral replication in human airway epithelia. Furthermore, HA mutants selected during viral replication in patients were likely to have less HA stability, apparently as a compensatory mechanism. These results begin to clarify the picture of the H5N1 human-adaptive mechanism.
  • Oxidative Rearrangement of Cyclobutanone Derived N,O-Ketals Leading to Pyrrolidone Derivatives, Kenichi Murai, Daisuke Endo, Norihito Kawashita, Tatsuya Takagi, Hiromichi Fujioka, CHEMICAL & PHARMACEUTICAL BULLETIN, CHEMICAL & PHARMACEUTICAL BULLETIN, 63(4), 245 - 247, Apr. 2015
    Summary:A halogen-induced oxidative rearrangement of N,O-ketals prepared from cyclobutanones, leading to pyrrolidone derivatives, is developed. The reaction proceeds via an iminium ether intermediate and, depending on the reaction medium, two types of pyrrolidone derivative, containing a halogen atom or hydroxyl group, can be obtained.
  • Chikungunya virus was isolated in Thailand, 2010, Mikiko Sasayama, Surachet Benjathummarak, Norihito Kawashita, Prasert Rukmanee, Suntaree Sangmukdanun, Promsin Masrinoul, Pannamthip Pitaksajjakul, Orapim Puiprom, Pitak Wuthisen, Takeshi Kurosu, Panjaporn Chaichana, Pannamas Maneekan, Kazuyoshi Ikuta, Pongrama Ramasoota, Tamaki Okabayashi, Pratap Singhasivanon, Natthanej Luplertlop, VIRUS GENES, VIRUS GENES, 49(3), 485 - 489, Dec. 2014
    Summary:Chikungunya fever (CHIKF) is an acute febrile illness caused by a mosquito-borne alphavirus, chikungunya virus (CHIKV). This disease re-emerged in Kenya in 2004, and spread to the countries in and around the Indian Ocean. The re-emerging epidemics rapidly spread to regions like India and Southeast Asia, and it was subsequently identified in Europe in 2007, probably as a result of importation of chikungunya cases. On the one hand, chikungunya is one of the neglected diseases and has only attracted strong attention during large outbreaks. In 2008-2009, there was a major outbreak of chikungunya fever in Thailand, resulting in the highest number of infections in any country in the region. However, no update of CHIKV circulating in Thailand has been published since 2009. In this study, we examined the viral growth kinetics and sequences of the structural genes derived from CHIKV clinical isolates obtained from the serum specimens of CHIKF-suspected patients in Central Thailand in 2010. We identified the CHIKV harboring two mutations E1-A226V and E2-I211T, indicating that the East, Central, and South African lineage of CHIKV was continuously circulating as an indigenous population in Thailand.
  • Meta-analysis of the Risk of Upper Gastrointestinal Hemorrhage with Combination Therapy of Selective Serotonin Reuptake Inhibitors and Non-steroidal Anti-inflammatory Drugs, Yoshinari Oka, Kousuke Okamoto, Norihito Kawashita, Yuko Shirakuni, Tatsuya Takagi, BIOLOGICAL & PHARMACEUTICAL BULLETIN, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 37(6), 947 - 953, Jun. 2014 , Refereed
    Summary:It is thought that both selective serotonin reuptake inhibitors (SSRIs) and non-steroidal anti-inflammatory drugs (NSAIDs) can cause the adverse reaction of upper gastrointestinal hemorrhage (UGIH). To evaluate differences in the probability of UGIH occurring when SSRIs, NSAIDs, or both combined are administered, the authors performed a systematic review of related articles and a meta-analysis of data in those articles, which were identified by searching the literature published between 1999 and 2012 using PubMed, Scirus, and Google Scholar. The odds ratios were calculated using the Mantel-Haenszel method. The integrated odds ratios for SSRIs only, NSAIDs only, and the combination were 1.73 (0.65-2.82), 2.55 (1.51-3.59), and 4.02 (2.89-5.15), respectively. Use of the combination resulted in an odds ratio 2.32 times higher than use of either alone. Since the combination of SSRIs and NSAIDs resulted in a significantly higher risk of UGIH than either type of drug alone, clinicians should avoid use of the combination as much as possible. If it is necessary to administer both kinds of drugs, the minimum dosage should be prescribed for the shortest time period possible, and patients, particularly elderly patients, should be closely monitored for development of UGIH and other complications.
  • Emerging Antigenic Variants at the Antigenic Site Sb in Pandemic A(H1N1)2009 Influenza Virus in Japan Detected by a Human Monoclonal Antibody, Mayo Yasugi, Ritsuko Kubota-Koketsu, Akifumi Yamashita, Norihito Kawashita, Anariwa Du, Ryo Misaki, Motoki Kuhara, Naphatsawan Boonsathorn, Kazuhito Fujiyama, Yoshinobu Okuno, Takaaki Nakaya, Kazuyoshi Ikuta, PLOS ONE, PLOS ONE, 8(10), Oct. 2013
    Summary:The swine-origin pandemic A(H1N1) 2009 virus, A(H1N1)pdm09, is still circulating in parts of the human population. To monitor variants that may escape from vaccination specificity, antigenic characterization of circulating viruses is important. In this study, a hybridoma clone producing human monoclonal antibody against A(H1N1) pdm09, designated 5E4, was prepared using peripheral lymphocytes from a vaccinated volunteer. The 5E4 showed viral neutralization activity and inhibited hemagglutination. 5E4 escape mutants harbored amino acid substitutions (A189T and D190E) in the hemagglutinin (HA) protein, suggesting that 5E4 recognized the antigenic site Sb in the HA protein. To study the diversity of Sb in A(H1N1) pdm09, 58 viral isolates were obtained during the 2009/10 and 2010/11 winter seasons in Osaka, Japan. Hemagglutination-inhibition titers were significantly reduced against 5E4 in the 2010/11 compared with the 2009/10 samples. Viral neutralizing titers were also significantly decreased in the 2010/11 samples. By contrast, isolated samples reacted well to ferret anti-A(H1N1) pdm09 serum from both seasons. Nonsynonymous substitution rates revealed that the variant Sb and Ca2 sequences were being positively selected between 2009/10 and 2010/11. In 7,415 HA protein sequences derived from GenBank, variants in the antigenic sites Sa and Sb increased significantly worldwide from 2009 to 2013. These results indicate that the antigenic variants in Sb are likely to be in global circulation currently.
  • A small compound targeting the interaction between nonstructural proteins 2B and 3 inhibits dengue virus replication, Sabar Pambudi, Norihito Kawashita, Supranee Phanthanawiboon, Magot Diata Omokoko, Promsin Masrinoul, Akifumi Yamashita, Kriengsak Limkittikul, Teruo Yasunaga, Tatsuya Takagi, Kazuyoshi Ikuta, Takeshi Kurosu, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 440(3), 393 - 398, Oct. 2013
    Summary:The non-structural protein NS2B/NS3 serine-protease complex of the dengue virus (DENV) is required for the maturation of the viral polyprotein. Dissociation of the NS2B cofactor from NS3 diminishes the enzymatic activity of the complex. In this study, we identified a small molecule inhibitor that interferes with the interaction between NS2B and NS3 using structure-based screening and a cell-based viral replication assay. A library containing 661,417 small compounds derived from the Molecular Operating Environment lead-like database was docked to the NS2B/NS3 structural model. Thirty-nine compounds with high scores were tested in a secondary screening using a cell-based viral replication assay. SK-12 was found to inhibit replication of all DENV serotypes (EC50=0.74-4.92 mu M). In silico studies predicted that SK-12 pre-occupies the NS2B-binding site of NS3. Steady-state kinetics using a fluorogenic short peptide substrate demonstrated that SK-12 is a noncompetitive inhibitor against the NS2B/NS3 protease. Inhibition to Japanese encephalitis virus by SK-12 was relatively weak (EC50 = 29.81 mu M), and this lower sensitivity was due to difference in amino acid at position 27 of NS3. SK-12 is the promising small-molecule inhibitor that targets the interaction between NS2B and NS3. (C) 2013 Elsevier Inc. All rights reserved.
  • A Practical Estimation Method for Analyzing Adverse Drug Reactions Using Data Mining, Yuko Shirakuni, Kousuke Okamoto, Etuko Uejima, Shigeki Inui, Jun-ichi Takahara, Takanori Ohgaru, Hiroyuki Yamasaki, Yushi Tian, Norihito Kawashita, Ran Inoue, Teruo Yasunaga, Tatsuya Takagi, THERAPEUTIC INNOVATION & REGULATORY SCIENCE, THERAPEUTIC INNOVATION & REGULATORY SCIENCE, 47(2), 235 - 241, Mar. 2013
    Summary:This study aimed to determine the potentially severe chemical properties of drugs that can cause adverse drug reactions (ADRs) such as erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) by using a data mining method. The study data were extracted from the Adverse Event Reporting System database of the FDA. EM was considered a mild reaction, and SJS and TEN were considered severe reactions. In this study, a new concept termed the "risk of aggravation" (ROA) was defined as whether a certain drug is more likely to cause severe adverse reactions than mild ones. Partial least squares and logistic regression analysis were applied using binary response variable ROAs. These analyses correctly predicted 50 of the 72 drugs associated with SJS and/or TEN and 28 of the 38 drugs associated with EM using binary chemical descriptors that are the same as those using the metric chemical descriptors.
  • A Practical Estimation Method for Analyzing Adverse Drug Reactions Using Data Mining, Yuko Shirakuni, Kousuke Okamoto, Etuko Uejima, Shigeki Inui, Jun-ichi Takahara, Takanori Ohgaru, Hiroyuki Yamasaki, Yushi Tian, Norihito Kawashita, Ran Inoue, Teruo Yasunaga, Tatsuya Takagi, THERAPEUTIC INNOVATION & REGULATORY SCIENCE, THERAPEUTIC INNOVATION & REGULATORY SCIENCE, 47(2), 235 - 241, Mar. 2013 , Refereed
    Summary:This study aimed to determine the potentially severe chemical properties of drugs that can cause adverse drug reactions (ADRs) such as erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) by using a data mining method. The study data were extracted from the Adverse Event Reporting System database of the FDA. EM was considered a mild reaction, and SJS and TEN were considered severe reactions. In this study, a new concept termed the "risk of aggravation" (ROA) was defined as whether a certain drug is more likely to cause severe adverse reactions than mild ones. Partial least squares and logistic regression analysis were applied using binary response variable ROAs. These analyses correctly predicted 50 of the 72 drugs associated with SJS and/or TEN and 28 of the 38 drugs associated with EM using binary chemical descriptors that are the same as those using the metric chemical descriptors.
  • Human Monoclonal Antibodies Broadly Neutralizing against Influenza B Virus, Mayo Yasugi, Ritsuko Kubota-Koketsu, Akifumi Yamashita, Norihito Kawashita, Anariwa Du, Tadahiro Sasaki, Mitsuhiro Nishimura, Ryo Misaki, Motoki Kuhara, Naphatsawan Boonsathorn, Kazuhito Fujiyama, Yoshinobu Okuno, Takaaki Nakaya, Kazuyoshi Ikuta, PLoS Pathogens, PLoS Pathogens, 9(2), Feb. 2013
    Summary:Influenza virus has the ability to evade host immune surveillance through rapid viral genetic drift and reassortment therefore, it remains a continuous public health threat. The development of vaccines producing broadly reactive antibodies, as well as therapeutic strategies using human neutralizing monoclonal antibodies (HuMAbs) with global reactivity, has been gathering great interest recently. Here, three hybridoma clones producing HuMAbs against influenza B virus, designated 5A7, 3A2 and 10C4, were prepared using peripheral lymphocytes from vaccinated volunteers, and were investigated for broad cross-reactive neutralizing activity. Of these HuMAbs, 3A2 and 10C4, which recognize the readily mutable 190-helix region near the receptor binding site in the hemagglutinin (HA) protein, react only with the Yamagata lineage of influenza B virus. By contrast, HuMAb 5A7 broadly neutralizes influenza B strains that were isolated from 1985 to 2006, belonging to both Yamagata and Victoria lineages. Epitope mapping revealed that 5A7 recognizes 316G, 318C and 321W near the C terminal of HA1, a highly conserved region in influenza B virus. Indeed, no mutations in the amino acid residues of the epitope region were induced, even after the virus was passaged ten times in the presence of HuMAb 5A7. Moreover, 5A7 showed significant therapeutic efficacy in mice, even when it was administered 72 hours post-infection. These results indicate that 5A7 is a promising candidate for developing therapeutics, and provide insight for the development of a universal vaccine against influenza B virus. © 2013 Yasugi et al.
  • Discovery of novel low-molecular-weight HIV-1 inhibitors interacting with cyclophilin A using in silico screening and biological evaluations, Yu-Shi Tian, Chris Verathamjamras, Norihito Kawashita, Kousuke Okamoto, Teruo Yasunaga, Kazuyoshi Ikuta, Masanori Kameoka, Tatsuya Takagi, JOURNAL OF MOLECULAR MODELING, JOURNAL OF MOLECULAR MODELING, 19(1), 465 - 475, Jan. 2013
    Summary:Cyclophilin A has attracted attention recently as a new target of anti-human immunodeficiency virus type 1 (HIV-1) drugs. However, so far no drug against HIV-1 infection exhibiting this mechanism of action has been approved. To identify new potent candidates for inhibitors, we performed in silico screening of a commercial database of more than 1,300 drug-like compounds by using receptor-based docking studies. The candidates selected from docking studies were subsequently tested using biological assays to assess anti-HIV activities. As a result, two compounds were identified as the most active. Specifically, both exhibited anti-HIV activity against viral replication at a low concentration and relatively low cytotoxicity at the effective concentration inhibiting viral growth by 50 %. Further modification of these molecules may lead to the elucidation of potent inhibitors of HIV-1.
  • Antigenic analysis of highly pathogenic avian influenza virus H5N1 sublineages co-circulating in Egypt, Yohei Watanabe, Madiha S. Ibrahim, Hany F. Ellakany, Norihito Kawashita, Tomo Daidoji, Tatsuya Takagi, Teruo Yasunaga, Takaaki Nakaya, Kazuyoshi Ikuta, JOURNAL OF GENERAL VIROLOGY, JOURNAL OF GENERAL VIROLOGY, 93, 2215 - 2226, Oct. 2012
    Summary:Highly pathogenic avian influenza virus H5N1 has spread across Eurasia and Africa, and outbreaks are now endemic in several countries, including Indonesia, Vietnam and Egypt. Continuous circulation of H5N1 virus in Egypt, from a single infected source, has led to significant genetic diversification with phylogenetically separable sublineages, providing an opportunity to study the impact of genetic evolution on viral phenotypic variation. In this study, we analysed the phylogeny of H5 haemagglutinin (HA) genes in influenza viruses isolated in Egypt from 2006 to 2011 and investigated the effect of conserved amino acid mutations in the HA genes in each of the sublineages on their antigenicity. The analysis showed that viruses in at least four sublineages still persisted in poultry in Egypt as of 2011. Using reverse genetics to generate HA-reassortment viruses with specific HA mutations, we found antigenic drift in the HA in two influenza virus sublineages, compared with the other currently co-circulating influenza virus sublineages in Egypt. Moreover, the two sublineages with significant antigenic drift were antigenically distinguishable. Our findings suggested that phylogenetically divergent H5N1 viruses, which were not antigenically cross-reactive, were co-circulating in Egypt, indicating that there was a problem in using a single influenza virus strain as seed virus to produce influenza virus vaccine in Egypt and providing data for designing more efficacious control strategies in H5N1-endemic areas.
  • Compliance Survey for Thalidomide Safety Use (part5); after Revision of TERMS, Yuko Shirakuni, Chizuko Hattori, Nobuyasu Yamaguchi, Teruyoshi Kubo, Norihito Kawashita, Tatsuya Takagi, Masao Nasu, PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, 21, 208 - 208, Aug. 2012 , Refereed
  • Frequency of D222G and Q223R Hemagglutinin Mutants of Pandemic (H1N1) 2009 Influenza Virus in Japan between 2009 and 2010, Mayo Yasugi, Shota Nakamura, Tomo Daidoji, Norihito Kawashita, Ririn Ramadhany, Cheng-Song Yang, Teruo Yasunaga, Tetsuya Iida, Toshihiro Horii, Kazuyoshi Ikuta, Kazuo Takahashi, Takaaki Nakaya, PLOS ONE, PLOS ONE, 7(2), Feb. 2012
    Summary:Background: In April 2009, a novel swine-derived influenza A virus (H1N1pdm) emerged and rapidly spread around the world, including Japan. It has been suggested that the virus can bind to both 2,3- and 2,6-linked sialic acid receptors in infected mammals, in contrast to contemporary seasonal H1N1 viruses, which have a predilection for 2,6-linked sialic acid. Methods/Results: To elucidate the existence and transmissibility of alpha 2,3 sialic acid-specific viruses in H1N1pdm, amino acid substitutions within viral hemagglutinin molecules were investigated, especially D187E, D222G, and Q223R, which are related to a shift from human to avian receptor specificity. Samples from individuals infected during the first and second waves of the outbreak in Japan were examined using a high-throughput sequencing approach. In May 2009, three specimens from mild cases showed D222G and/or Q223R substitutions in a minor subpopulation of viruses infecting these individuals. However, the substitutions almost disappeared in the samples from five mild cases in December 2010. The D187E substitution was not widespread in specimens, even in May 2009. Conclusions: These results suggest that alpha 2,3 sialic acid-specific viruses, including G222 and R223, existed in humans as a minor population in the early phase of the pandemic, and that D222 and Q223 became more dominant through human-to-human transmission during the first and second waves of the epidemic. These results are consistent with the low substitution rates identified in seasonal H1N1 viruses in 2008.
  • Recent Advances in the Development of Small-Molecule Compounds Targeting HIV-1 gp41 as Membrane Fusion Inhibitors, Norihito Kawashita, Yu-Shi Tian, U. Chandimal de Silva, Kousuke Okamoto, Tatsuya Takagi, MINI-REVIEWS IN ORGANIC CHEMISTRY, MINI-REVIEWS IN ORGANIC CHEMISTRY, 9(1), 20 - 26, Feb. 2012 , Refereed
    Summary:Over the past few years, remarkable progress has been made in the development of human immunodeficiency virus (HIV) membrane fusion inhibitors. The focus has been on peptide inhibitors, which were developed by mimicking HIV sequences; however, these types of inhibitors generally lack oral bioavailability and are expensive. Therefore, development of small-molecule inhibitors has gained importance and recently progressed. This paper reviews the rapid advancements in the development of small-molecule HIV inhibitors over the last decade.
  • Development of Novel Evaluation Method to Anti-influenza Drug Resistance using Docking Study, Norihito Kawashita, Masashi Yasuda, Yu-Shi Tian, Kousuke Okamoto, Masaya Kawase, Teruo Yasunaga, Tatsuya Takagi, ANTIVIRAL RESEARCH, ANTIVIRAL RESEARCH, 90(2), A71 - A71, May 2011 , Refereed
  • Acquisition of Human-Type Receptor Binding Specificity by New H5N1 Influenza Virus Sublineages during Their Emergence in Birds in Egypt, Yohei Watanabe, Madiha S. Ibrahim, Hany F. Ellakany, Norihito Kawashita, Rika Mizuike, Hiroaki Hiramatsu, Nogluk Sriwilaijaroen, Tatsuya Takagi, Yasuo Suzuki, Kazuyoshi Ikuta, PLOS PATHOGENS, PLOS PATHOGENS, 7(5), May 2011
    Summary:Highly pathogenic avian influenza A virus subtype H5N1 is currently widespread in Asia, Europe, and Africa, with 60% mortality in humans. In particular, since 2009 Egypt has unexpectedly had the highest number of human cases of H5N1 virus infection, with more than 50% of the cases worldwide, but the basis for this high incidence has not been elucidated. A change in receptor binding affinity of the viral hemagglutinin (HA) from alpha 2,3- to alpha 2,6-linked sialic acid (SA) is thought to be necessary for H5N1 virus to become pandemic. In this study, we conducted a phylogenetic analysis of H5N1 viruses isolated between 2006 and 2009 in Egypt. The phylogenetic results showed that recent human isolates clustered disproportionally into several new H5 sublineages suggesting that their HAs have changed their receptor specificity. Using reverse genetics, we found that these H5 sublineages have acquired an enhanced binding affinity for alpha 2,6 SA in combination with residual affinity for alpha 2,3 SA, and identified the amino acid mutations that produced this new receptor specificity. Recombinant H5N1 viruses with a single mutation at HA residue 192 or a double mutation at HA residues 129 and 151 had increased attachment to and infectivity in the human lower respiratory tract but not in the larynx. These findings correlated with enhanced virulence of the mutant viruses in mice. Interestingly, these H5 viruses, with increased affinity to alpha 2,6 SA, emerged during viral diversification in bird populations and subsequently spread to humans. Our findings suggested that emergence of new H5 sublineages with alpha 2,6 SA specificity caused a subsequent increase in human H5N1 influenza virus infections in Egypt, and provided data for understanding the virus's pandemic potential.
  • Design and evaluation of antiretroviral peptides corresponding to the C-terminal heptad repeat region (C-HR) of human immunodeficiency virus type 1 envelope glycoprotein gp41, Bongkot Soonthornsata, Yu-Shi Tian, Piraporn Utachee, Sompong Sapsutthipas, Panasda Isarangkura-na-ayuthaya, Wattana Auwanit, Tatsuya Takagi, Kazuyoshi Ikuta, Pathom Sawanpanyalert, Norihito Kawashita, Masanori Kameoka, VIROLOGY, VIROLOGY, 405(1), 157 - 164, Sep. 2010
    Summary:Two alpha-helical heptad repeats. N-HR and C-HR, located in the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp41, play an important role in membrane fusion by forming a 6-helix bundle. C34, a peptide mimicking C-HR, inhibits the formation of the 6-helix bundle, thus, it has potential as a novel antiretroviral compound In order to improve the inhibitory effect of C34 on HIV-1 replication, we designed new C34-derived peptides based on computational analysis of the stable conformation of the 6-helix bundle Newly designed peptides showed a stronger inhibitory effect on the replication of recombinant viruses containing CRF01_AE, subtype B or subtype C Env than C34 or a fusion inhibitor, T-20 In addition, these peptides inhibited the replication of a T-20-resistant virus We propose that these peptides could be applied to develop novel antiretroviral compounds to inhibit the replication of various subtypes of HIV-I as well as of T-20-resistant variants (C) 2010 Elsevier Inc All rights reserved
  • Nonlinear classification of hERG channel inhibitory activity by unsupervised classification method, Shinnosuke Hidaka, Hiroyuki Yamasaki, Yoshihiro Ohmayu, Akiko Matsuura, Kousuke Okamoto, Norihito Kawashita, Tatsuya Takagi, JOURNAL OF TOXICOLOGICAL SCIENCES, JOURNAL OF TOXICOLOGICAL SCIENCES, 35(3), 393 - 399, Jun. 2010
    Summary:The side effects that occur in the central nervous system and circulatory system due to medicines are expected to be prevented by research and development. However, many of the compounds in medicines have the possibility of causing arrhythmia, and methods developed to detect this problem at the early stage of drug development are not always successful. In the present study, we classified drug compounds according to their activity using only structural information. To classify compounds, we used a self-organizing map (SUM), which is a nonlinear unsupervised classification method. We first analyzed a small-scale dataset, and an excellent classification result was obtained. We then applied our method to a large-scale dataset containing numerous inert compounds and were again able to classify the compounds according to their activity. Both classifications showed some compound activity, although a few differences between the two SOM maps were seen.
  • Structure of the prion protein and its gene: an analysis using bioinformatics and computer simulation., Akikazu Sakudo, Guangai Xue, Norihito Kawashita, Yasuhisa Ano, Tatsuya Takagi, Hideharu Shintani, Yasuharu Tanaka, Takashi Onodera, Kazuyoshi Ikuta, Current protein & peptide science, Current protein & peptide science, 11(2), 166 - 79, Mar. 2010
    Summary:Prion protein (PrP) gene encodes cellular PrP (PrPC), a glycosylphosphatidylinositol (GPI)-anchored cell membrane protein indispensable for infections of prion, which causes Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE) in cattle, and scrapie in sheep. Although PrPC is known to be converted into an abnormal isoform (PrPSc) upon prion infection and play an important role in prion diseases, the mechanisms involved remain unclear, partly due to the insolubility of PrPSc, which prevents experimental biochemical and biophysical analyses. Recently, with improvements in computer power and methods, computer analyses have been contributing more to prion studies. A comparison of PrP gene sequences revealed mutations and polymorphisms in the open reading frame (ORF) of the human PrP gene related to prion diseases. In contrast, little mutations or polymorphisms related to susceptibility to BSE were found in the ORF of the bovine PrP gene, though relationships between insertion/deletion (Ins/Del) polymorphisms of the PrP gene promoter and susceptibility to BSE have been found. Our results have shown that the specific protein 1 (Sp1) plays important role in the activity of PrP gene promoter, which is influenced by polymorphisms in the Sp1 binding sites. The potential structural dynamics of PrP have been simulated by computational methods such as molecular dynamics (MD) and quantum mechanics (QM). The proposed mechanisms of conversion have revealed new insights in prion diseases. In this review, we will introduce the gene structure, polymorphisms, and potential structural dynamics of PrP revealed by basic and advanced computational analyses. The possible contribution of these methods to elucidation of the pathogenicity of prion diseases and functions of PrPC is discussed.
  • Highly conserved sequences for human neutralization epitope on hemagglutinin of influenza A viruses H3N2, H1N1 and H5N1: Implication for human monoclonal antibody recognition, Akifumi Yamashita, Norihito Kawashita, Ritsuko Kubota-Koketsu, Yuji Inoue, Yohei Watanabe, Madiha S. Ibrahim, Shoji Ideno, Mikihiro Yunoki, Yoshinobu Okuno, Tatsuya Takagi, Teruo Yasunaga, Kazuyoshi Ikuta, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 393(4), 614 - 618, Mar. 2010 , Refereed
    Summary:The epitope sequences within the hemagglutinin (HA) of influenza A virus H3N2 at amino acid residues 173-181 and 227-239 that forms anti-parallel beta-sheet structure are similarly recognized by human monoclonal antibodies (HuMAbs), B-1 and D-1 that we recently obtained using the peripheral blood lymphocytes from two influenza-vaccinated volunteers. Both HuMAbs showed strong global neutralization of H3N2 strains. Here we show the significant conservation of the beta-sheet region consisting of the above-mentioned two epitope regions in H3N2. In addition, we also identified the corresponding regions with similar structure in other subtypes such as H1N1 and H5N1. These two regions are similarly located underneath the receptor-binding sites of individual subtypes. Analysis of those regions using sequences available from the Influenza Virus Resource at the National Center for Biotechnology Information revealed that compared with those in the known neutralizing epitopes A-E, those sequences were fairly conserved in human H3N2 (n = 7955), swine H1N1 (n = 360) and swine H3N2 (n = 235); and highly conserved in human H1N1 (n = 2722), swine-origin pandemic H1N1 (n = 1474), human H5N1 (n = 319) and avian H5N1 (n = 2349). Phylogenetic tree for these regions formed clearly separable clusters for HIM, H3N2 and H5N1, irrespective of different host origin. These data may suggest a possible significance of those regions for development of alternative vaccine that could induce neutralizing antibodies reactive against wide-range of influenza virus strains. (C) 2010 Elsevier Inc. All rights reserved.
  • Structure of the Prion Protein and Its Gene: An Analysis Using Bioinformatics and Computer Simulation, Akikazu Sakudo, Guangai Xue, Norihito Kawashita, Yasuhisa Ano, Tatsuya Takagi, Hideharu Shintani, Yasuharu Tanaka, Takashi Onodera, Kazuyoshi Ikuta, CURRENT PROTEIN & PEPTIDE SCIENCE, CURRENT PROTEIN & PEPTIDE SCIENCE, 11(2), 166 - 179, Mar. 2010 , Refereed
    Summary:Prion protein (PrP) gene encodes cellular PrP (PrPC), a glycosylphosphatidylinositol (GPI)-anchored cell membrane protein indispensable for infections of prion, which causes Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE) in cattle, and scrapie in sheep. Although PrPC is known to be converted into an abnormal isoform (PrPSc) upon prion infection and play an important role in prion diseases, the mechanisms involved remain unclear, partly due to the insolubility of PrPSc, which prevents experimental biochemical and biophysical analyses. Recently, with improvements in computer power and methods, computer analyses have been contributing more to prion studies. A comparison of PrP gene sequences revealed mutations and polymorphisms in the open reading frame (ORF) of the human PrP gene related to prion diseases. In contrast, little mutations or polymorphisms related to susceptibility to BSE were found in the ORF of the bovine PrP gene, though relationships between insertion/deletion (Ins/Del) polymorphisms of the PrP gene promoter and susceptibility to BSE have been found. Our results have shown that the specific protein 1 (Sp1) plays important role in the activity of PrP gene promoter, which is influenced by polymorphisms in the Sp1 binding sites. The potential structural dynamics of PrP have been simulated by computational methods such as molecular dynamics (MD) and quantum mechanics (QM). The proposed mechanisms of conversion have revealed new insights in prion diseases. In this review, we will introduce the gene structure, polymorphisms, and potential structural dynamics of PrP revealed by basic and advanced computational analyses. The possible contribution of these methods to elucidation of the pathogenicity of prion diseases and functions of PrPC is discussed.
  • Anionic polymer, poly(methyl vinyl ether-maleic anhydride)-coated beads-based capture of human influenza A and B virus., Akikazu Sakudo, Koichi Baba, Megumi Tsukamoto, Atsuko Sugimoto, Takashi Okada, Takanori Kobayashi, Norihito Kawashita, Tatsuya Takagi, Kazuyoshi Ikuta, Bioorganic & medicinal chemistry, Bioorganic & medicinal chemistry, 17(2), 752 - 7, Jan. 15 2009 , Refereed
    Summary:An anionic magnetic beads-based method was developed for the capture of human influenza A and B viruses from nasal aspirates, allantoic fluid and culture medium. A polymer, poly(methyl vinyl ether-maleic anhydride) [poly(MVE-MA)], was used to endow magnetic beads with a negative charge and bioadhesive properties. After incubation with samples containing human influenza virus, the beads were separated from supernatants by applying a magnetic field. The adsorption [corrected] of the virus by the beads was confirmed by hemagglutinin assay, immunochromatography, Western blotting, egg infection, and cell infection. Successful capture was proved using 5 H1N1 influenza A viruses, 10 H3N2 influenza A viruses, and 6 influenza B viruses. Furthermore, the infectivity in chicken embryonated eggs and Madin-Darby canine kidney (MDCK) cells of the captured human influenza virus was similar to that of the total viral quantity of starting materials. Therefore, this method of capture using magnetic beads coated with poly(MVE-MA) can be broadly used for the recovery of infectious human influenza viruses.
  • Screening of HIV membrane fusion peptide by using computational chemistry, Norihito Kawashita, JOURNAL OF PHARMACOLOGICAL SCIENCES, JOURNAL OF PHARMACOLOGICAL SCIENCES, 109, 32P - 32P, 2009 , Refereed
  • Enhancement of ordinal CoMFA by ridge logistic partial least squares, Takanori Ohgaru, Ryo Shimizu, Kosuke Okamoto, Norihito Kawashita, Masaya Kawase, Yuko Shirakuni, Rika Nishikiori, Tatsuya Takagi, JOURNAL OF CHEMICAL INFORMATION AND MODELING, JOURNAL OF CHEMICAL INFORMATION AND MODELING, 48(4), 910 - 917, Apr. 2008
    Summary:Conventional comparative molecular field analysis (CoMFA) requires at least 3 orders of experimental data, such as IC50 and K-i, to obtain a good model, although practically there are many screening assays where biological activity is measured only by rating scale. To improve three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis, we developed in this study a modified ordinal classification-oriented CoMFA using partial-least-squares generalized linear regression and ridge estimation. The modified Logistic CoMFA was validated using a corticosteroid binding globulin receptor binding data set, a benchmark for 3D-QSAR, and an acetylcholine esterase inhibitor data set. Our results show that modification of Logistic CoMFA enhanced both prediction accuracy and 3D graphical analysis. In addition, the 3D graphical analysis of the modified Logistic CoMFA was much improved. This improvement resulted in more accurate information on the binding mode between proteins and ligands than in the case of conventional CoMFA.
  • Enhancement of ordinal CoMFA by ridge logistic partial least squares, Takanori Ohgaru, Ryo Shimizu, Kosuke Okamoto, Norihito Kawashita, Masaya Kawase, Yuko Shirakuni, Rika Nishikiori, Tatsuya Takagi, JOURNAL OF CHEMICAL INFORMATION AND MODELING, JOURNAL OF CHEMICAL INFORMATION AND MODELING, 48(4), 910 - 917, Apr. 2008 , Refereed
    Summary:Conventional comparative molecular field analysis (CoMFA) requires at least 3 orders of experimental data, such as IC50 and K-i, to obtain a good model, although practically there are many screening assays where biological activity is measured only by rating scale. To improve three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis, we developed in this study a modified ordinal classification-oriented CoMFA using partial-least-squares generalized linear regression and ridge estimation. The modified Logistic CoMFA was validated using a corticosteroid binding globulin receptor binding data set, a benchmark for 3D-QSAR, and an acetylcholine esterase inhibitor data set. Our results show that modification of Logistic CoMFA enhanced both prediction accuracy and 3D graphical analysis. In addition, the 3D graphical analysis of the modified Logistic CoMFA was much improved. This improvement resulted in more accurate information on the binding mode between proteins and ligands than in the case of conventional CoMFA.
  • Application of partial least square on quantitative analysis of L-, D-, and DL-tartaric acid by terahertz absorption spectra, Rika Nishikiori, Mariko Yamaguchi, Keisuke Takano, Tokujiro Enatsu, Masahiko Tani, U. Chandimal de Silva, Norihito Kawashita, Tatsuya Taragi, Shotaro Morimoto, Masanori Hangyo, Masaya Kawase, CHEMICAL & PHARMACEUTICAL BULLETIN, CHEMICAL & PHARMACEUTICAL BULLETIN, 56(3), 305 - 307, Mar. 2008
    Summary:Absorption spectra of polycrystalline L-, D-, and DL-tartaric acid have been measured by terahertz time domain spectroscopy (THz-TDS). Different absorption bands are observed for DL-tartaric acid and its enantiomers (L- and D-tartaric acid). This result shows that the THz-TDS can be used for distinguishing between DL-tartaric acid and enantiomers (L- and D-tartaric acid). Moreover, partial least square (PLS) can be found to improve the quantitation of L-tartaric acid in L- and DL-tartaric acid mixture by THz-TDS.
  • Application of partial least square on quantitative analysis of L-, D-, and DL-tartaric acid by terahertz absorption spectra, Rika Nishikiori, Mariko Yamaguchi, Keisuke Takano, Tokujiro Enatsu, Masahiko Tani, U. Chandimal De Silva, Norihito Kawashita, Tatsuya Takagi, Shotaro Morimoto, Masanori Hangyo, Masaya Kawase, Chemical and Pharmaceutical Bulletin, Chemical and Pharmaceutical Bulletin, 56(3), 305 - 307, Mar. 2008 , Refereed
    Summary:Absorption spectra of polycrystalline L-, D-, and DL-tartaric acid have been measured by terahertz time domain spectroscopy (THz-TDS). Different absorption bands are observed for DL-tartaric acid and its enantiomers (L- and D-tartaric acid). This result shows that the THz-TDS can be used for distinguishing between DL-tartaric acid and enantiomers (L- and D-tartaric acid). Moreover, partial least square (PLS) can be found to improve the quantitation of L-tartaric acid in L- and DL-tartaric acid mixture by THz-TDS. © 2008 Pharmaceutical Society of Japan.
  • Highly regioselective nucleophilic carbon-carbon bond formation on furans and thiophenes initiated by Pumerer-type reaction, S Akai, N Kawashita, H Satoh, Y Wada, K Kakiguchi, Kuriwaki, I, Y Kita, ORGANIC LETTERS, ORGANIC LETTERS, 6(21), 3793 - 3796, Oct. 2004 , Refereed
    Summary:(GRAPHICS) The reactions of (phenyLsulfinyl)furans or -thiophenes with carbon nucleophiles in the presence of trifluoroacetic anhydride allowed the nucleophilic installation of carbon functional groups on the furan and thiophene nuclei with complete regioselectivity.
  • Regioselective synthesis of 2,3,5-trisubstituted indoles from p-sulfinylaniline by dual use of the sulfinyl group, S Akai, N Kawashita, N Morita, Y Nakamura, K Iio, Y Kita, HETEROCYCLES, HETEROCYCLES, 58, 75 - 78, Nov. 2002
    Summary:A novel and convergent synthesis of 2,3,5-trisubstituted indoles (6) from p-sulfinylaniline (1) is described. The single p-sulfinyl group was repeatedly employed in two ways; viz., the construction of the 2,3-disubstituted indole/indoline skeleton and the introduction of a carbon substituent at the C-5 position.

Works

  • 多剤耐性HIVにおける将来的な変異・構造予測と新規抗HIV薬開発
  • 多剤耐性HIVにおける将来的な変異・構造予測と新規抗HIV薬開発
  • Research Collaboration Center on Emerging and Re-emerging Infections
  • Research Collaboration Center on Emerging and Re-emerging Infections

Misc

  • プラズマ処理水中の過硝酸の分解に関する量子化学計算, 川嶋裕介, 川下理日人, 川下理日人, 高木達也, 高木達也, 井川聡, 北野勝久, 応用物理学会春季学術講演会講演予稿集(CD-ROM), 64th, ROMBUNNO.16p‐313‐8,   2017 03 , http://jglobal.jst.go.jp/public/201702257083612462
  • 活性酸素種によるアミノ酸残基への酸化反応機構の量子化学計算, 川嶋裕介, 川下理日人, 川下理日人, 高木達也, 高木達也, 井川聡, 北野勝久, 応用物理学会春季学術講演会講演予稿集(CD-ROM), 64th, ROMBUNNO.16p‐313‐9,   2017 03 , http://jglobal.jst.go.jp/public/201702291920105664
  • Evaluation of Novel Anti-Dengue Candidates Using In Silico and In Vitro Approaches, TIAN Yu‐Shi, MATSUDA Hitoshi, LIU Xinzhe, KAWASHITA Norihito, KAWASHITA Norihito, TAKAGI Tatsuya, TAKAGI Tatsuya, 日本薬学会年会要旨集(CD-ROM), 137th, ROMBUNNO.26G‐ISMS06,   2017 , http://jglobal.jst.go.jp/public/201702242103033242
  • Analyses of protein-ligand interaction of BACE1 and its ligands using fragment molecular orbital method, HASHIMOTO Yuji, KAWASHITA Norihito, MORIWAKI Hirotomo, TIAN Yu‐Shi, TAKAGI Tatsuya, 構造活性相関シンポジウム講演要旨集, 44th, 49‐50,   2016 11 16 , http://jglobal.jst.go.jp/public/201602228635903082
  • Constructing prediction models of adverse drug reactions using machine learning, MORIUCHI Hiroaki, TIAN Yu‐Shi, MORIWAKI Hirotomo, AOKI Satoshi, TAKAYAMA Nobuki, KAWASHITA Norihito, HIBI Takayuki, TAKAGI Tatsuya, 構造活性相関シンポジウム講演要旨集, 44th, 31‐32,   2016 11 16 , http://jglobal.jst.go.jp/public/201602241042520012
  • Novel Polymerase Gene Mutations for Human Adaptation in Clinical Isolates of Avian H5N1 Influenza Viruses, ARAI Yasuha, ARAI Yasuha, KAWASHITA Norihito, DAIDOJI Tomo, IBRAHIM Madiha, TAKAHASHI Kazuo, SUZUKI Yasuo, NAKAYA Takaaki, SHIODA Tatsuo, IKUTA Kazuyoshi, WATANABE Yohei, WATANABE Yohei, 日本ウイルス学会学術集会プログラム・抄録集, 64th, 139,   2016 09 30 , http://jglobal.jst.go.jp/public/201602235500029292
  • 状態空間モデルによるサリドマイド製剤安全管理手順(TERMS)における患者対象調査の時系列データ解析, 加藤平太, 白國優子, 川下理日人, 田雨時, 高木達也, 那須正夫, 社会薬学, 35, Supplement, 111, 111,   2016 08 29 , http://jglobal.jst.go.jp/public/201602213002976341
  • 分子記述子計算ソフトウェアmordredの開発, 森脇寛智, 川下理日人, 川下理日人, TIAN Yu‐Shi, 高木達也, 高木達也, ケモインフォマティクス討論会予稿集(Web), 39th, ROMBUNNO.Y4(J‐STAGE),   2016 , 10.11545/ciqs.2016.0_Y4, http://jglobal.jst.go.jp/public/201602226619679330
  • 分子軌道計算によるスペクトルの精度の検討, 諏訪志典, 川嶋裕介, 川下理日人, 川下理日人, 藤居由基, TIAN Yu‐Shi, 藤岡弘道, 有澤光弘, 高木達也, 高木達也, ケモインフォマティクス討論会予稿集(Web), 39th, ROMBUNNO.P9(J‐STAGE),   2016 , 10.11545/ciqs.2016.0_P9, http://jglobal.jst.go.jp/public/201602252376482162
  • 化合物の光分解性予測モデルの構築に関する基礎的検討, 松山裕美, 川下理日人, 川下理日人, TIAN Yu‐Shi, 岡本晃典, 高木達也, 高木達也, ケモインフォマティクス討論会予稿集(Web), 39th, ROMBUNNO.P16(J‐STAGE),   2016 , 10.11545/ciqs.2016.0_P16, http://jglobal.jst.go.jp/public/201602291732483542
  • フラグメント分子軌道法による病原性蛋白質と宿主因子との相互作用解析, 川下理日人, 川下理日人, TIAN Yu‐Shi, 高木達也, 高木達也, 分子科学討論会講演プログラム&要旨(Web), 10th, ROMBUNNO.3G17 (WEB ONLY),   2016 , http://jglobal.jst.go.jp/public/201702273408507040
  • Chance Correlationを可能な限り回避する回帰手法の開発と応用, 八田朋子, 川下理日人, 川下理日人, 田雨時, 高木達也, 高木達也, ケモインフォマティクス討論会予稿集(Web), 38th, 124‐125(J‐STAGE),   2015 10 01 , 10.11545/ciqs.2015.0_124, http://jglobal.jst.go.jp/public/201502206701780644
  • Novel insights enantioselective binding of IMiDs to cereblon using in silico docking simulations., MURAI Takahiro, KAWASHITA Norihito, TIAN Yushi, TAKAGI Tatsuya, 構造活性相関シンポジウム講演要旨集, 43rd, 52‐55,   2015 09 , http://jglobal.jst.go.jp/public/201502215364318371
  • SPECT脳血流画像に基づく機械学習を用いた疾患判別予測モデルの構築, 阪本健也, 幡生あすか, 高木達也, 岡本晃典, 川下理日人, 日本薬学会年会要旨集(CD-ROM), 135th, 2, ROMBUNNO.27PA-PM010, 289,   2015 03 , http://jglobal.jst.go.jp/public/201502202001941110
  • ドッキングスタディとボルツマン分布を組み合わせた薬剤耐性変異評価法の開発, 上田智弘, 川下理日人, 岡本晃典, 高木達也, 情報化学討論会講演要旨集(Web), 37th, P06(J-STAGE),   2014 11 20 , 10.11545/ciqs.2014.0_P06, http://jglobal.jst.go.jp/public/201502268282962685
  • SPECT脳血流画像に基づく機械学習を用いた疾患判別, 阪本 健也, 幡生 あすか, 岡本 晃典, 川下 理日人, 高木 達也, 日本薬学会年会要旨集, 134年会, 2, 297, 297,   2014 03
  • 【ここまできた!抗ウイルス薬】 3次元定量的構造活性相関(3D-QSAR)を利用した抗HCV薬の探索, 高木 達也, 川下 理日人, ファルマシア, 49, 11, 1090, 1094,   2013 11 , 10.14894/faruawpsj.49.11_1090
  • Identification of a novel inhibitor against dengue virus NS2B/NS3 protease by a structure-based study, SABAR Pambudi, KAWASHITA Norihito, SUPRANEE Phanthanawiboon, MAGOT Omokoko, PROMSIN Masrinoul, KRIENGSAK Limkittikul, YASUNAGA Teruo, TAKAGI Tatsuya, IKUTA Kazuyoshi, KUROSU Takeshi, 日本ウイルス学会学術集会プログラム・抄録集, 61st, 161,   2013 10 29 , http://jglobal.jst.go.jp/public/201302202285639561
  • In Sillico解析を応用したフラビウイルスプロテーゼ阻害剤の同定, Pambudi Sabar, 川下 理日人, 安永 照雄, 高木 達也, Limkittikul Kriengsak, 生田 和良, 黒須 剛, 日本獣医学会学術集会講演要旨集, 156回, 266, 266,   2013 08
  • 薬学部生と既卒者が共に学習できる薬学統計学のeラーニングサイトの構築について, 宮崎 恭行, 村田 俊郎, 岡本 晃典, 川下 理日人, 白井 達也, 上島 悦子, 高木 達也, 日本薬学会年会要旨集, 133年会, 4, 230, 230,   2013 03
  • クラスタリングの反復を用いた生体影響に関するQSARモデルの構築, 河南 潤, 伊藤 光文, 伊藤 雅士, 岡本 晃典, 川下 理日人, 高木 達也, 日本薬学会年会要旨集, 133年会, 2, 201, 201,   2013 03
  • 医薬学データ用統計解析プログラム、MEPHASの更新について(その3), 福井 大介, 田 雨時, 岡本 晃典, 川下 理日人, 後藤 直久, 安永 照雄, 高木 達也, 日本薬学会年会要旨集, 133年会, 2, 323, 323,   2013 03
  • 副作用予測を指向したリバースフィッティングシステムの構築とその医薬品への適用, 長田 真衣, 川下 理日人, 田 雨時, 岡本 晃典, 安永 照雄, 高木 達也, 日本薬学会年会要旨集, 132年会, 4, 159, 159,   2012 03
  • 医薬学データ用統計解析プログラム、MEPHASの更新について(その2), 福井 大介, 田 雨時, 岡本 晃典, 川下 理日人, 後藤 直久, 安永 照雄, 高木 達也, 日本薬学会年会要旨集, 132年会, 4, 161, 161,   2012 03
  • サリドマイド安全使用のための薬剤管理に関する調査(その4), 高木 達也, 白國 優子, 川下 理日人, 平井 啓, 岡本 晃典, 服部 千鶴子, 山口 進康, 那須 正夫, 日本薬学会年会要旨集, 132年会, 4, 290, 290,   2012 03
  • 社会における薬剤リスクに対する認識調査, 服部 千鶴子, 白国 優子, 平井 啓, 須磨 一夫, 岡本 晃典, 川下 理日人, 山口 進康, 高木 達也, 那須 正夫, 日本薬学会年会要旨集, 132年会, 4, 290, 290,   2012 03
  • フラグメント分子軌道法を利用したHIV gp41の相互作用解析, 川下 理日人, 田 雨時, 岡本 晃典, 安永 照雄, 高木 達也, 日本エイズ学会誌, 13, 4, 435, 435,   2011 11
  • シクロフィリンAをターゲットとする新たな候補を見つけるための分子ドッキング法の検討(Investigation of molecular docking method in order to find novel candidates targeting cyclophilin A), 田 雨時, 川下 理日人, 岡本 晃典, Verathamjamras Chris, 安永 照雄, 生田 和良, 亀岡 正典, 高木 達也, 日本エイズ学会誌, 13, 4, 482, 482,   2011 11
  • 医薬品による副作用予測を目的とした、リバースフィッティングシステムの構築, 長田 真衣, 川下 理日人, 田 雨時, 荒井 由貴, 岡本 晃典, 安永 照雄, 高木 達也, 日本薬学会年会要旨集, 131年会, 4, 125, 125,   2011 03
  • CypAをターゲットとする抗HIV-1低分子化合物のin Silico探索, 田 雨時, 川下 理日人, Chris Verathamjamras, 杉本 裕昌, 岡本 晃典, 安永 照雄, 亀岡 正典, 高木 達也, 日本薬学会年会要旨集, 131年会, 4, 126, 126,   2011 03
  • 医薬学データ用統計解析プログラム、MEPHASの更新について, 福井 大介, 田 雨時, 岡本 晃典, 川下 理日人, 後藤 直久, 安永 照雄, 高木 達也, 日本薬学会年会要旨集, 131年会, 4, 127, 127,   2011 03
  • サリドマイド安全使用のための薬剤管理に関する調査(その2), 高木 達也, 川下 理日人, 白国 優子, 平井 啓, 服部 千鶴子, 岡本 晃典, 藤原 拓也, 山口 進康, 那須 正夫, 日本薬学会年会要旨集, 131年会, 4, 305, 305,   2011 03
  • 要管理医薬品の回収・指導に関する調査, 白國 優子, 藤原 拓也, 須磨 一夫, 平井 啓, 服部 千鶴子, 岡本 晃典, 川下 理日人, 山口 進康, 那須 正夫, 高木 達也, 日本薬学会年会要旨集, 131年会, 4, 305, 305,   2011 03
  • 計量薬学 信頼と保証を科学する 多変量解析法を用いた疾患・副作用の診断、予後予測支援, 高木 達也, 原田 雅史, 高橋 由武, 岡本 晃典, 川下 理日人, 白國 優子, 渡辺 俊輔, 井上 藍, 幡生 あすか, 日本薬学会年会要旨集, 130年会, 1, 210, 210,   2010 03
  • シクロフィリンAを標的としたフラグメントスクリーニングによる抗HIV薬の探索研究, 川下 理日人, 田 雨時, 杉本 裕昌, 岡本 晃典, 安永 照雄, 高木 達也, 日本薬学会年会要旨集, 130年会, 2, 246, 246,   2010 03
  • HIV1膜融合阻害剤としての2-Aryl 5-(4-Oxo-3-phenethyl-2-thioxo thiazolidinylidenemethyl)furansのQSAR解析, 田 雨時, 川下 理日人, 岡本 晃典, 安永 照雄, 高木 達也, 日本薬学会年会要旨集, 130年会, 2, 254, 254,   2010 03
  • 化学物質の環境運命予測を目指した、光分解・加水分解反応データベースの構築, 栗花落 昇平, 岡本 晃典, 尾形 直紀, 川下 理日人, 高原 淳一, 高木 達也, 日本薬学会年会要旨集, 129年会, 3, 264, 264,   2009 03
  • ドッキングスタディを利用したインフルエンザノイラミニダーゼ阻害剤の薬剤耐性評価, 安田 匡志, 川下 理日人, 柏田 理恵, 田 雨時, 岡本 晃典, 川瀬 雅也, 安永 照雄, 高木 達也, 日本薬学会年会要旨集, 129年会, 4, 142, 142,   2009 03
  • 医薬化学 目指せ!第2世代のHIVインテグラーゼ阻害剤, 川下 理日人, ファルマシア, 44, 12, 1216, 1217,   2008 12
  • HIV膜融合阻害剤C34に関する構造活性相関研究, 川下 理日人, 田 雨時, 安田 匡志, 岡本 晃典, 錦織 理華, 亀岡 正典, 安永 照雄, 生田 和良, 川瀬 雅也, 高木 達也, 日本薬学会年会要旨集, 128年会, 2, 53, 53,   2008 03
  • HIV gp41の蛋白質間相互作用計算によるアミノ酸残基と膜融合阻害活性との相関, 川下 理日人, 田 雨時, 中村 昇太, 岡本 晃典, 後藤 直久, de Silva, U. Chandimal, 亀岡 正典, 川瀬 雅也, 安永 照雄, 生田 和良, 高木 達也, 日本エイズ学会誌, 9, 4, 405, 405,   2007 11
  • Computational Studies on Relationship with Protein-Protein Interaction Energy of HIV-1 gp41 and Its Inhibitory Activity of Membrane Fusion, Kawashita, N, Tian, Y.-s, Nakamura, S, Kawaguchi, A, Yamashita, N, Okamoto, K, de Silva, U. C, Kameoka, M, Yasunaga, T, Ikuta, K, Takagi, T,   2007 01
  • Improvement of nonparametric regression method based on the PLS algorithm., Nishikiori Rika, Yonekura Satoshi, Okamoto Kousuke, Ohgaru Takanori, Matsuura Akiko, Ochi Yukino, Morimoto Shotaro, Saito Tadashi, Kawashita Norihito, Yasunaga Teruo, Kawase Masaya, Takagi Tatsuya, Symposium on Chemical Information and Computer Sciences, 2007, 0, JK03, JK03,   2007 , http://ci.nii.ac.jp/naid/130004574961
    Summary:Since some of the descriptors for QSAR data show nonlinear relationships between the descriptors and biological activities, they should be analyzed by nonlinear analysis methods. However, the algorithm of nonparametric regression methods is complicated and is difficult to show the contributions of QSAR descriptors. Hence, we proposed a new simple nonparametric regression method, which was named SANORA, before. This method is based on the additive model as well as penalized local regression. In addition, this method has comparatively simple algorithm which means that the contributions of predictive variables can be easily estimated. We would like to introduce this method and propose the solution of the overfitting problem when it is applied to the data set which has many predictive variables. In order to avoid this problem and to obtain results faster, we applied the PLS algorithm to reduce dimensions of the data: The latent variables were used as predictive variables for the SANORA analysis of ACE inhibition activity data. As a result of cross-validation, the predictive performance of the constructed model became better.
  • Refinement of Regression Discrimination Analysis, Yamasaki Hiroyuki, Ohgaru Takanori, Okamoto Kousuke, Kawashita Norihito, Takahara Junichi, Nishikiori Rika, Kawase Masaya, Yasunaga Teruo, Takagi Tatsuya, Symposium on Chemical Information and Computer Sciences, 2007, 0, JP19, JP19,   2007 , http://ci.nii.ac.jp/naid/130004574984
    Summary:A method called Regression Discrimination Analysis (RDA) has been developed for the discrimination of ordered categorical data. The method (RDA method) has the advantages of simultaneously considering any numbers of classes and faster computation than other methods. However, the RDA method is not utilized because the RDA method is inferior in recognition and prediction. The RDA method has two problems. First, although the RDA method needs parameters called class values, the class values are not specified. For this reason, the most adequate class values have to be determined for each time. Secondly, the borders of the RDA method are also not specified. The change of the borders has great influence on the result of discrimination. In this study, we suggest the optimized class values which are determined by searching for the normality in the data belonging each class value. We have refined the RDA method to some extent in this study.
  • A Concise Synthesis of Bisbenzannelated Spiroketals via Aromatic Pummerer-type Reaction, Kakiguchi, K, Kuriwaki, I, Dohi, T, Kawashita, N, Akai, S, Kita, Y,   2006 08
  • Synthesis of Polysubstituted Indoles by Iterative Use of the Aromatic Pummerer-type Reaction, Kawashita, N, Kakiguchi, K, Wada, Y, Akai, S, Kita, Y,   2005 08
  • Highly Regioselective, Nucleophilic Substitution on Electron-Sufficient Heteroaromatic Compounds through the Aromatic Pummerer-Type Reaction, Kawashita, N, Akai, S, Kita, Y,   2004 08
  • A Computational Approach to Search Active Peptides as Membrane Fusion Inhibitors of HIV-1, Yu-Shi Tian, Norihito Kawashita, Chris Verathamjamras, Kousuke Okamoto, Teruo Yasunaga, Masanori Kameoka, Tatsuya Takagi, ANTIVIRAL RESEARCH, 90, 2, A76, A77,   2011 05 , Refereed, 10.1016/j.antiviral.2011.03.166
  • A QSAR Study using GA-PLS on anti-HIV-1 Small Molecules Targeting Cyclophilin A, Tian Yushi, Norihito Kawashita, Rie Kashiwada, Hiromasa Sugimoto, Teruo Yasunaga, Kousuke Okamoto, Tatsuya Takagi, PLS '09: PROCEEDINGS OF THE 6TH INTERNATIONAL CONFERENCE ON PARTIAL LEAST SQUARES AND RELATED METHODS, 334, 337,   2009 , Refereed
    Summary:The discovery of the fact that Gag capsid (CA) protein of Human immunodeficiency virus type 1 (HIV-1) interacts with host proteins such as cyclophilin A (CypA) is capable of providing us a new target to develop anti-HIV-1 drugs. Since the complex formations between CypA and CA can be inhibited by an immunosuppressive drug cyclosporine A (CsA), some non-immunosuppressive CsA like compounds might be candidates for new class argents of anti-HIV/AIDS treatment. However, the anti-HIV activities of most small molecules designed to alternate CsA still remain to be confirmed by viral experiments. We thus constructed QSAR models using GA-PLS method, and these models might be helpful to classify the unchecked compounds and also might provide us some new ideas on designing de novo molecule.
  • Computational studies of gp41 6-helix bundle: Do stabilized energy of HIV membrane fusion inhibitor C34 and interaction energy of gp41 6-helix bundle have good correlation with their inhibitory activity?, Norihito Kawashita, Yu-Shi Tian, Masashi Yasuda, U. Chandimal de Silva, Rie Kashiwada, Shota Nakamura, Naohisa Goto, Rika Nishikiori, Kousuke Okamoto, Masanori Kameoka, Teruo Yasunaga, Masaya Kawase, Kazuyoshi Ikuta, Tatsuya Takagi, ANTIVIRAL RESEARCH, 78, 2, A42, A42,   2008 05 , Refereed, 10.1016/j.antiviral.2008.01.080

Awards & Honors

  •   2009 , Poster Award at the 32th Symposium on Chemical Information and Computer Science

Research Grants & Projects

  • The Other Research Programs, Development of Novel Organic Reaction