3D-QSAR Studies of S-DABO Derivatives as Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors

Background: S-dihydro-alkyloxy-benzyl-oxopyrimidines (S-DABOs) as non-nucleoside reverse transcriptase inhibitors have received considerable attention during the last decade due to their high potency against HIV-1. Methods: In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) of a series of 38 S-DABO analogues developed in our lab was studied using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). The Docking/MMFF94s computational protocol based on the co-crystallized complex (PDB ID: 1RT2) was used to determine the most probable binding mode and to obtain reliable conformations for molecular alignment. Statistically significant CoMFA (q(2)=0.766 and r(2)=0.949) and CoMSIA (q(2)=0.827 and r(2)=0.974) models were generated using the training set of 30 compounds on the basis of hybrid docking-based and ligand-based alignment. Results: The predictive ability of CoMFA and CoMSIA models was further validated using a test set of eight compounds with predictive r(pred)(2) values of 0.843 and 0.723, respectively. Conclusion: The information obtained from the 3D contour maps can be used in designing new S-DABO derivatives with improved HIV-1 inhibitory activity.