3D-QSAR and docking-based combined in silico study on C-5 methyl substituted 4-arylthio and 4-aryloxy-3-iodopyridin-2-(1H)-one as HIV-1 RT inhibitors

Abstract

The development of novel inhibitors of HIV-1 RT would be helpful for management of AIDS. 3D-QSAR studies were performed on C-5 methyl substituted 4-arylthio and 4-aryloxy-3-iodopyridin-2-(1H)-one. QSAR analyses used to understand the structural factors affecting inhibitory activity of pyridinone substituted derivatives. Pharmacophore alignment and scoring engine (PHASE) was used to develop predictive common pharmacophore hypothesis (CPH), which were further validated. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA) based 3D-QSAR models were derived using pharmacophore-based alignment. A structurally diverse set of 58 molecules was divided into 36 molecules of test set and rest of the 22 molecules of training set. Both CoMFA (Q2 = 0.512, r2 = 0.97, rpred2 = 0.562) and CoMSIA (Q2 = 0.502, r2 = 0.931, rpred2 = 0.512) gave correlative and predictive abilities on both training and test set. The 3D-QSAR of both studies were indicated steric, electrostatic and hydrogen bond acceptor effects contribute to the inhibitory activity. The docking studies were also carried out wherein the active and inactive molecules were docked into inhibitor-binding pocket of wild-type and Try188Leu mutant HIV-1 reverse transcriptase crystal structure to analyses the enzyme inhibition interaction. The outcome of the study could be used for the rational design of potent and selective HIV-1 reverse transcriptase inhibitors.