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Overhauser效应（TRNOE）测量研究了羟保泰松（OXY）、硝苯砜-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.我们结合了从构象分析仪与分子动力学和采样（CAMDAS）计算和实验NOE光谱测量获得的距离信息，以进行提取的“结合构象”的药物结合到HSA分子的网站I。我们已经获得了网站I结合药物OXY，DNS-LYS，FU，1，17，和5“选定的构象”分别。对于OXY，获得一种选定的构象异构体（conf 9）。以conf 9的基本结合构象为“模板”，选择DNS-LYS和FU的结合构象，通过计算机三维图形学方法对17种DNS-LYS和5种FU的结合构象进行拟合，得到DNS-LYS（conf 144）和FU（conf 21）的结合构象。对这三种药物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点是相对疏水的侧链如丁基、赖氨酸或呋喃环覆盖了疏水部分如苯基或丹磺酰基，或者它们采取相邻的紧凑结构。这种结合分子动力学计算和NOE信息的方法，为获得药物与HSA结合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.