Docking-based CoMFA and CoMSIA studies on naphthyl-substituted diarylpyrimidines as NNRTIs

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) play a significant role in anti-HIV drug development. A series of naphthyl-substituted diarylpyrimidines with most EC50 values in the nanomolar range was reported as potent NNRTIs by our lab. In order to obtain the quantitative structure-activity relationship (QSAR) that can guide rational lead optimization, CoMFA and CoMSIA studies were carried out. Docking study based on the co-crystallized complex (PDB ID: 3MEC) was utilized as an approach to obtain reliable conformations for molecular alignment. Two different molecular alignments were performed, resulting in two CoMFA models and 34 CoMSIA models. The CoMSIA models correspond to all the possible combinations among five fields: steric, electrostatic, hydrophobic, hydrogen bond donor, and hydrogen bond acceptor. Highly predictive models were achieved, in which the statistically reliable CoMFA model had a q(2) of 0.743 and an r(2) of 0.980, whereas the best CoMSIA model had a q(2) of 0.713 and an r(2) of 0.969. The best models were rigorously validated with an external test set, which gave satisfactory predictive r(2) values for CoMFA and CoMSIA models: 0.85 and 0.83, respectively. Contour maps obtained from selected models revealed important structural features and some rational guidance for further optimization.