Analysis of binding conformations of drugs to human serum albumin (site I and site II) by NMR measurements and computational calculations

通过 NMR 测量和计算分析药物与人血清白蛋白（位点 I 和位点 II）的结合构象

• 批准号: 10672024
• 负责人: HIRONO Shuichi
• 金额: $ 1.22万
• 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: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10672024/
• 关键词: Molecular Dynamics; CAMDAS; SUPERPOSE; TRNOE; HAS; Protein Binding; Site I; Site II; 分子重ね合わせ法; NMR

(1) The binding conformations of drugs to site I and site II of HAS has been investigated by CAMDAS, SUPERPOSE and TRNOE experiments. We have combined distance information obtained from CAMDAS and TRNOE to perform an extraction of a "binding conformer" for drugs binding to the HAS (site I and site II ).(2) Site I binding drugsFor BMT, one selected conformer (BMT354) was obtained. The basic binding conformer structure of BMT354 was taken as a "template" to choose binding conformers for FUCI and IM. Consequently, we could efficiently select one binding conformer for FUCI and IM.(3) Site II binding drugsFor tolmetin (TLM), only one conformer (TLM 53) among conformers generated by CAMDAS satisfied the distance restraint conditions obtained from NOESY. The structure of the TLM (conf53) was taken as a "template" to choose binding conformers for other drugs by molecular overlay. We could efficiently select one binding conformer for ETH-A, R-IB, S-IB, R-KP and S-KP.(4) Then, we constructed the complex structure of drugs (BMT354, TLM53) and HAS based on the crystal structure of HAS using Flexi Dock program implemented in SYBYL (Tripos).This method of combining MD calculation, SUPERPOSE and TRNOE measurements suggested to an extremely effective method for obtaining steric conformation for drugs bound to HAS.Binding conformer of the drugs in the binding site (site I and site II ) of HAS was used to probe the drug-HAS complementary interactions.

(1)用CAMDAS、SUPERPOSE和TRNOE实验研究了药物与HAS位点I和位点II的结合构象。我们结合了从CAMDAS和TRNOE获得的距离信息，以提取与HAS结合的药物的“结合构象异构体”（位点I和位点II）。(2)位点I结合药物对于BMT，获得了一种选择的构象异构体（BMT 354）。以BMT 354的基本结合构象结构为“模板”，选择FUCI和IM的结合构象。因此，我们可以有效地选择一个结合构象的FUCI和IM。(3)对于托美丁（TLM），CAMDAS生成的构象中只有一个（TLM 53）满足NOESY得到的距离约束条件。以TLM（conf 53）的结构为“模板”，通过分子叠加选择与其他药物结合的构象。我们可以有效地选择ETH-A，R-IB，S-IB，R-KP和S-KP的一种结合构象。(4)然后，我们构建了药物的复杂结构，（BMT 354，TLM 53）和HAS的晶体结构，使用SYBYL（Tripos）中实现的Flexi Dock程序。该方法结合MD计算，SUPERPOSE和TRNOE测量是获得药物与HAS结合的空间构象的一种非常有效的方法。药物在结合部位的结合构象（位点I和位点II）用于探测药物-HAS互补相互作用。

项目成果

K.Iwase and S.Hirono: "Estimation of active conformations of drugs by a new molecular superposing procedure"J.Comput-Aided Mol.Des.. 13(5). 499-512 (1999)

K.Iwase 和 S.Hirono：“通过新的分子叠加程序估计药物的活性构象”J.Comput-Aided Mol.Des.. 13(5)。

K. Iwase: "Estimation of active conformations of drugs by a new molecular superposing procedure"J. Comput-Aided Mol. Des.. 13・5. 499-512 (1999)

K. Iwase：“通过新的分子叠加程序估计药物的活性构象”J. Comput-Aided Mol. 13・5 (1999)。

Y.Matsushita, et al.: "Determination of Binding Conformations of Drugs to Human Serum Albumin by Transferred Nuclear Overhauser Effect Measurements and Conformational Analysis Using High-temperature Molecular Dynamics Calculations"J.Pharm.Sci.. 87(3). 379

Y.Matsushita 等人：“通过转移核欧沃豪瑟效应测量和使用高温分子动力学计算的构象分析来测定药物与人血清白蛋白的结合构象”J.Pharm.Sci. 87(3)。

Y. Matsushita: "Determination of Binding Conformations of Drugs to Human Serum Albumin by Transferred Nuclear Overhauser Effect Measurements and Conformational Analyses Using High-temperature Molecular Dynamics Calculations"J. Pharm. Sci.. 87・3. 379-386 (

Y. Matsushita：“通过转移核欧沃豪塞效应测量和使用高温分子动力学计算的构象分析来确定药物与人血清白蛋白的结合构象” J. Sci. 87・3（

V. T. G. Chuang: "Helix 6 of subdomain IIIA of human serum albumin is the region primarily photolabeled by ketoprofen, an aryipropionic acid NSAID containing a benzophenone moiety"Biochim. Biophys. Acta.. 1434・1. 18-30 (1999)

V. T. G. Chuang：“人血清白蛋白子结构域 IIIA 的螺旋 6 是主要由酮洛芬（一种含有二苯甲酮部分的芳基丙酸 NSAID）进行光标记的区域”Biochim Biophys. 1434・1。