Docking-based 3D-QSAR study of HIV-1 integrase inhibitors

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 r2cv = 0.728, non-cross validation r2ncv = 0.934 and predictive r2pred = 0.708. The best CoMSIA model yielded a cross validation r2cv = 0.794, non-cross validation r2ncv = 0.928 and predictive r2pred = 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.

Graphical abstract2D representation of interactions between magnesium ion and molecule 32 obtained from docking to HIV-1 IN active site. This docked conformation of highly active molecule 32 was used for alignment of all the molecules in the series, for CoMFA and COMSIA analysis. Figure optionsDownload full-size imageDownload as PowerPoint slide