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

用分子动力学(MD)计算和转移核欧豪瑟效应(TRNOE)方法研究了羟苯丁酮(OXY)、丹参酮-L赖氨酸(DNS-LYS)和速尿(FU)与人血清白蛋白(HSA)的结合构象。我们将从构象分析仪获得的距离信息与分子动力学和采样(CAMDAS)计算和实验NOE光谱测量相结合，对药物与HSA分子I位结合的“结合构象”进行了提取。对于I位结合药物，我们分别获得了1，17和5个“选择构象”。对于Oxy，得到了一个选择的构象(Conf9)。以conf9的基本结合构象结构为“模板”，对17个dns-lys和5-FU构象进行三维计算机图形拟合，得到一个分别与dns-lys(Conf144)和FU(Conf21)结合的构象。这三种药物的结合构象的拟合结果表明，HSA结合药物的空间结构的一个特征是相对疏水的侧链，如丁基、赖氨基或呋喃环，覆盖了疏水部分，如苯基或丹磺基，或它们具有邻近的紧凑结构。这种结合MD计算和NOE信息的方法为获得与HSA结合的药物的空间构象提供了一种非常有效的方法。

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.