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Determination of Binding Conformation of Drugs to Human Serum Albumin by Molecular Dynamics Calculations and Transferred Nuclear Overhauser Effect Measurements

通过分子动力学计算和转移核奥豪塞效应测量测定药物与人血清白蛋白的结合构象

基本信息

批准号：
07672325
负责人：
HIRONO Shuichi
金额：
$ 1.6万
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：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07672325/
关键词：
Molecular Dynamics Conformation Analysis NMR TRNOE Human Serum Albumin Binding Conformation

项目摘要

The binding conformations of oxyphenbutazone (OXY), Nepsilon-dansyl-L-lysine (DNS-LYS), and furosemide (FU) to human serum albumin (HSA) have been investigated by molecular dynamics (MD) calculation and transferred nuclear Overhauser effect (TRNOE) measurements. We have combined distance information obtained from Conformational Analyzer with Molecular Dynamics And Sampling (CAMDAS) calculation and experimental NOE spectroscopy measurements to perform an extraction of a "binding conformer" for drugs binding to the HSA molecular site I.We have obtained for the site I binding drugs OXY,DNS-LYS,and FU,1,17, and 5 "selected conformer" respectively. For OXY,one selected conformer (conf9) was obtained. The basic binding conformer structure of conf9 was taken as a "template" to choose binding conformers for DNS-LYS and FU.By fitting the 17 DNS-LYS and 5 FU conformers to the "template" using three dimensional computer graphics, we can efficiently obtaine one binding conformer respectively for DNS-LYS (conf144) and FU (conf21). Results from fitting the binding conformers of these three drug suggests that a feature of the steric structure of HSA biding drugs is that comparatively hydrophobic side chains, such as butyl group, lysine group or furan ring, cover hydrophobic portions such as phenyl or dansyl group, or that they take a neighboring compact structure. This method of combining MD calculation and NOE information suggested to an extremely effective method for obtaining steric conformation for drugs bound to HSA.

通过分子动力学（MD）计算和转移核欧沃豪塞效应（TRNOE）测量研究了羟保泰松（OXY）、奈普西隆-丹磺酰-L-赖氨酸（DNS-LYS）和呋塞米（FU）与人血清白蛋白（HSA）的结合构象。我们结合分子动力学和采样构象分析仪（CAMDAS）计算和实验NOE光谱测量获得的距离信息，提取了与HSA分子位点I结合的药物的“结合构象异构体”。我们分别获得了位点I结合药物的OXY、DNS-LYS和FU、1、17和5“选定构象异构体”。对于OXY，获得了一个选定的构象异构体(conf9)。以conf9的基本结合构象异构体结构为“模板”，选择DNS-LYS和FU的结合构象异构体。通过利用三维计算机图形学将17个DNS-LYS和5个FU构象异构体拟合到“模板”上，我们可以有效地分别获得DNS-LYS（conf144）和FU（conf21）的1个结合构象异构体。对这三种药物的结合构象异构体进行拟合的结果表明，HSA结合药物的空间结构特征是相对疏水的侧链，如丁基、赖氨酸基团或呋喃环，覆盖疏水部分如苯基或丹酰基，或者它们采取相邻的致密结构。这种结合 MD 计算和 NOE 信息的方法提出了一种极其有效的方法来获得与 HSA 结合的药物的空间构象。