Receptor-based Molecular Designs of DABO Derivatives as HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors

A series of 46 dihydro-alkoxy-benzyl-oxopyrimidines (DABOs), a class of highly potent non-nucleoside reverse transcriptase inhibitors (NNRTIs), was studied by molecular docking followed by comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA). The results showed that the H-bonding interactions between the C=O and NH of the pyrimidine ring and Lys101, hydrophobic interactions between R, R1, X sites of ligands and neighboring amino acid residuals, and the electrostatic interactions between ligands and His235 and Lys101 residues were the dominant factors affecting the binding affinities. Based on an optimal docking conformation, 3D-QSAR models of 46 DABO derivatives were developed. The r2 and cross-validated r2 (q2) of an optimal CoMSIA model were 0.862 and 0.532, respectively. Based on the QSAR studies, 9 new compounds were designed by the method of LeapFrog. The binding energies and docking scores (GScore) of 9 new compounds were better than that of a template molecule with the highest observed activity. The results showed that the molecular designs of DABOs should be focused on the hydrophobic interactions with the bottom of the binding pocket as well as van der Waals interactions with the entrance of binding pocket.