Molecular modeling studies of dihydro-alkyloxy-benzyl-oxopyrimidines (DABOs) as non-nucleoside inhibitors of HIV-1 reverse transcriptase using 3D-QSAR, Topomer CoMFA and molecular docking simulations

Abstract

The human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is generally regarded as a target for the treatment of acquired immune deficiency syndrome (AIDS). Non-nucleoside RT inhibitors (commonly known as NNRTIs) are currently being used in the treatment of HIV-1 infections. In this work, a series of NNRTIs were studied using a combination of molecular modeling techniques including three-dimensional quantitative structure–activity relationship (3D-QSAR), Topomer CoMFA and molecular docking simulations. The best optimum comparative molecule field analysis (CoMFA) model yielded a leave-one-out correlation coefficient (q²) and a non-cross-validated correlation coefficient (r²) of 0.636 and 0.993, respectively. The respective q² and r² of the best comparative molecular similarity indices analysis (CoMSIA) model were 0.655 and 0.998. The models were validated by test sets, and predicted correlation coefficients (r_pred²) of 0.907 and 0.886 obtained from the CoMFA and CoMSIA models, thus judging the robustness of the model. The analysis of Topomer CoMFA obtained a q² of 0.546 and a r_pred² value of 0.718 which suggested the model had a good predictive ability (q² > 0.2). The results indicated the steric, hydrophobic and electrostatic fields play key roles in the models. Molecular docking elucidated the conformations of the compounds and key amino acid residues at the docking pocket of RT protein.