QSAR Study of Cyclic Urea Type HIV-1 PR Inhibitors Using Ab Initio MO Calculation of Their Complex Structures with HIV-1 PR

Abstract

A quantitative structure-activity relationship study was carried out on a series of cyclic urea type HIV-1 protease inhibitors. In order to determine the atomic and electronic mechanisms in detail, three-dimensional and electronic descriptors were calculated with the molecular dynamics and ab initio fragment molecular orbital calculation of the whole complex structure of HIV-1 protease with each inhibitor. Two descriptors showing correlation with the inhibitory potency were the total interaction energy and the change in the accessible surface area on complex formation with HIV-1 protease. The major contributions to the total electronic interaction energy were found to be from Asp25/25′, Asp30/30′ and Ile50/50′. The interaction energy with Asp30/30' was nicely correlated with the total electronic interaction energy and also with the charge transfer from Asp30/30′, which is in close contact with the substituted moiety in each inhibitor. As well as the hydrophobic interaction, the charge redistribution among the inhibitor and surrounding residues was suggested to govern the variation in the inhibitory potency. The results obtained in this work can help us to reinterpret the classical QSAR descriptors proposed by Garg et al.