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Determination of binding conformations of drugs to HAS and modeling of drug-HAS complex

药物与 HAS 结合构象的测定以及药物-HAS 复合物的建模

基本信息

批准号：
12672095
负责人：
HIRONO Shuichi
金额：
$ 1.54万
依托单位：
Kitasato University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12672095/
关键词：
Molecular Dynamics SUPERPOSE Human Serum Albumin Binding Conformation Site I Site II NMR Docking 分子動力額計算

项目摘要

(1) It was carried out about the TRNOE measurement, the conformational analysis of binding drug (CAMDAS method, SUPERPOSE method etc.), contraction of the complex model by Flexi Dock method and molecular dynamics (MD) simulation of the complex model in the water solution.(2) Construction of complex models were carried out by docking (SYBYL Ver6.7: Tripos Co.) between binding conformations og drugs and HAS.I) Site I complex modelsIt could think about drugs which did binding at site I with hydrogen bond or electrostatic interaction between the part of negative charges of drugs and LYS199, ARG222, ARG257. It is found that benzen ring and alkyl group of drug forms hydrophobic interactions with PHE211, TRP214, PHE223, LEU238, ILE264, LEU276 and LEU290.II) Site II complex modelsThe electrostatic interactions between the part of negative charges and ARG410, TYR411 and ARG485 were suggested at the site II binding drugs. Furthermore, the part of hydrophobic of the drugs could think what fit did in hydrophobic pocket composed of VAL415, LEU423, LEU460 and PHE488 and so on.(3) Molecular dynamics (MD) simulation of complex modelsIt was suggested that the interaction (hydrogen bond, electrostatic and hydrophobic) shown with (2)-I) and (2)-II) were influence even in the water solution as a results of carrying out MD simulation about the constructed complex models (BMT354-site I and TLM53-site II) in the water.

(1)进行了TRNOE测量、结合药物的构象分析（CAMDAS法、SUPERPOSE法等）、Flexi Dock法对配合物模型的收缩以及配合物模型在水溶液中的分子动力学（MD）模拟。(2)通过药物结合构象与HAS的对接（SYBYL Ver6.7: Tripos Co.）构建复杂模型。I位点复合体模型可以考虑在I位点发生氢键结合或药物部分负电荷与LYS199、ARG222、ARG257静电相互作用的药物。发现药物的苯环和烷基与PHE211、TRP214、PHE223、LEU238、ILE264、LEU276和LEU290形成疏水相互作用。II位点配合物模型部分负电荷与ARG410、TYR411和ARG485在II位点结合药物处存在静电相互作用。此外，在由VAL415、LEU423、LEU460和PHE488等组成的疏水口袋中，药物的疏水部分可以想象适合的作用。(3)复杂模型的分子动力学（MD）模拟通过对已构建的复杂模型（BMT354-site I和TLM53-site II）在水中进行分子动力学模拟，表明(2)-I和(2)-II所示的相互作用（氢键、静电和疏水）即使在水溶液中也会受到影响。