Centre for Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, SAS Nagar, 160062 Punjab, India.
Eur J Med Chem. 2009 Nov;44(11):4276-87. doi: 10.1016/j.ejmech.2009.07.010. Epub 2009 Jul 16.
In this study, 3-aroyl-1,1-dioxo-1,4,2-benzodithiazine and 4-chloro-N-(4-oxopyrimidin-2-yl)-2-mercaptobenzenesulfonamide derivatives (HIV-1 integrase inhibitors) were used for CoMFA and CoMSIA to determine the substructures required for the activity of these molecules. To explore the binding mode of inhibitors, docking studies were done and docked conformation of highly active molecule was used as template for alignment. The best CoMFA model yielded the cross validation r(2)(cv)=0.728, non-cross validation r(2)(ncv)=0.934 and predictive r(2)(pred)=0.708. The best CoMSIA model yielded a cross validation r(2)(cv)=0.794, non-cross validation r(2)(ncv)=0.928 and predictive r(2)(pred)=0.59. It was found that steric (CoMFA) and hydrophobic fields (CoMSIA) have large contribution towards the inhibitory activity than the other fields. Docking and 3D-QSAR studies have provided clues to a better understanding of interaction between the inhibitors and HIV-1 integrase.
在这项研究中，使用了 3-芳酰基-1,1-二氧代-1,4,2-苯并二硫杂环戊烯和 4-氯-N-(4-氧代嘧啶-2-基)-2-巯基苯磺酰胺衍生物（HIV-1 整合酶抑制剂）进行 CoMFA 和 CoMSIA，以确定这些分子活性所需的亚结构。为了探索抑制剂的结合模式，进行了对接研究，并将高活性分子的对接构象用作对齐的模板。最佳的 CoMFA 模型产生了交叉验证 r(2)(cv)=0.728、非交叉验证 r(2)(ncv)=0.934 和预测 r(2)(pred)=0.708。最佳的 CoMSIA 模型产生了交叉验证 r(2)(cv)=0.794、非交叉验证 r(2)(ncv)=0.928 和预测 r(2)(pred)=0.59。结果发现，立体（CoMFA）和疏水场（CoMSIA）对抑制活性的贡献大于其他场。对接和 3D-QSAR 研究为更好地理解抑制剂与 HIV-1 整合酶之间的相互作用提供了线索。
