Construction of a fused grid-based CYP2C19-Template system and the application |
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| Affiliation: | 1. Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan;2. Non-Clinical Regulatory Science, Applied Research & Operations, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan;3. Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, 980-8578, Japan;4. Division of Risk Assessment, National Institute of Health Sciences, Tonomachi 3-25-26, Kawasaki-ku, Kawasaki, 210-9501, Japan;1. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan;2. Kobe City Medical Center General Hospital, Kobe, Hyogo, 650-0047, Japan;1. Department of Toxicology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan;2. Department of Cancer Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan;3. Laboratory of Public Health, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki, Gunma, 370-0033, Japan;4. School of Pharmaceutical Sciences, Ohu University, 31-1 Misumido, Tomita-machi, Koriyama, Fukushima, 963-8611, Japan;1. Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan;2. School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan;3. National Institute of Health Sciences, Kawasaki-ku, Kawasaki, Kanagawa, 210-9501, Japan;1. Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-Cho, Hirakata, Osaka, 573-0101, Japan;2. Pharmaceutical Business Division, Sumika Chemical Analysis Service, Ltd., Osaka, 554-0022, Japan;1. Division of Medicinal Safety Science, National Institute of Health Sciences, Kawasaki, 210-9501, Japan;2. Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Doshisha Women''s College of Liberal Arts, Kyotanabe, 610-0395, Japan;3. Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan;4. Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, 980-8573, Japan;5. Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan;6. Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, 980-8574, Japan;7. Department of Dermatology, School of Medicine, Nara Medical University, Kashihara, 634-8522, Japan |
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| Abstract: | A ligand-accessible space in the CYP2C19 active site was reconstituted as a fused grid-based Template with the use of structural data of the ligands. An evaluation system of CYP2C19-mediated metabolism has been developed on Template with the introduction of the idea of Trigger-residue initiated ligand-movement and fastening. Reciprocal comparison of the data of simulation on Template with experimental results suggested a unified way of the interaction of CYP2C19 and its ligands through the simultaneous plural-contact with Rear-wall of Template. CYP2C19 was expected to have a room for ligands between vertically standing parallel walls termed Facial-wall and Rear-wall, which were separated by a distance corresponding to 1.5-Ring (grid) diameter size. The ligand sittings were stabilized through contacts with Facial-wall and the left-side borders of Template including specific Position 29 or Left-end after Trigger-residue initiated ligand-movement. Trigger-residue movement is suggested to force ligands to stay firmly in the active site and then to initiate CYP2C19 reactions. Simulation experiments for over 450 reactions of CYP2C19 ligands supported the system established. |
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| Keywords: | CYP2C19-mediated metabolism Fused-grid Template Inhibition Poor and good substrates Simulation of ligand-interaction on Template 2D" },{" #name" :" keyword" ," $" :{" id" :" pc_CEBMWKGXvp" }," $$" :[{" #name" :" text" ," _" :" two-dimensional 3D" },{" #name" :" keyword" ," $" :{" id" :" pc_vrhBG5zEiV" }," $$" :[{" #name" :" text" ," _" :" three-dimensional BaP" },{" #name" :" keyword" ," $" :{" id" :" pc_MynUe7BnHO" }," $$" :[{" #name" :" text" ," _" :" benzo[a]pyrene CYP" },{" #name" :" keyword" ," $" :{" id" :" pc_bhdwQuDvUM" }," $$" :[{" #name" :" text" ," _" :" cytochrome P450 PAH" },{" #name" :" keyword" ," $" :{" id" :" pc_Arzyb5X4vb" }," $$" :[{" #name" :" text" ," _" :" polyaromatic hydrocarbon S-MTPPA" },{" #name" :" keyword" ," $" :{" id" :" pc_ISqA2htbJR" }," $$" :[{" #name" :" text" ," _" :" S-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid |
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