Journal Name: Letters in Drug Design & Discovery
Author(s): Yueping Wang, Jie Chang, Jiangyuan Wang, Peng Zhong, Yufang Zhang, Christopher Cong Lai, Yanping He*.
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. In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) of a series of S-DABOs analogues developed in our lab was studied using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). Docking simulation based on the co-crystallized complex (PDB ID: 1RT2) were employed to determine the most probable binding mode and to obtain most reliable conformations for molecular alignment. Statistically significant CoMFA (q2=0.766 and r2=0.949) and CoMSIA (q2=0.827 and r2=0.974) models were generated using the training set on the basis of hybrid docking-based and ligand-based alignment. The predictive ability of CoMFA and CoMSIA models were further validated using a test set of eight compounds with predictive r2pred values of 0.843 and 0.723, respectively. The information obtained from the 3D contour maps can be used in designing new S-DABOs derivatives with improved HIV-1 inhibitory activity.