Multidimensional QSAR Modeling of Amprenavir Derivatives as HIV-Protease Inhibitors

Abstract

A computational study has been performed on a series of 55 compounds having (S)-N-(3-(N-(cyclopen-tyl-methyl) substituted-phenylsulfonamido)-2-hydroxypropyl) acetamide backbone as HIV-1 protease inhibitors. Various combinations of these specific inhibitors fragments were formed by breaking them at central ali-cyclic single bonds, while retaining the core. Standard Topomer 3D models were automatically constructed for each fragment, and a set of steric and electrostatic fields was generated for each set of topomers. The models generated showed r 2 of 0.811 and crossvalidated r 2 (q 2) of 0.608. The other method used were Quasar and Raptor based on receptor-modelling concept (6D-QSAR) and this explicitly allows for the simulation of the induced fit, that yielded r 2 of 0.574, cross-validated r 2 (q 2) of 0.504 and predictive r 2 (p 2) of 0.895 averaged over 200 models. This study has suggested the various type of substituent that can be attached to the core. The information obtained from these 3-D contour maps can be used for the design of amprenavir ana-logs possessing better protease inhibitory activity.