Molecular modeling and computer-aided molecular design of highly potent HIV-1 RT inhibitor in the class of diarylpyrimidine derivatives

In this work, computer aided molecular design and quantum chemical calculations were applied to investigate the structural basis of selected diarylpyrimidine derivatives (DAPYs) as highly potent anti-HIV-1 reverse transcriptase (RT) agents. To identify the specific interactions of DAPYs in wild type (WT) and double mutation (K103N/Y181C) HIV-1 RT binding pockets, molecular docking using Autodock 4.02 was performed. The results show that the docked conformation reveal a good ability to reproduce the X-ray bound conformation with the root mean square deviations (rmsd) less than 1.0 A for WT and K103N/Y181C HIV-1 RT binding pockets. Then, the obtained docking results of all DAPY derivatives were carried out to investigate their orientations and binding interactions in the WT and K103N/Y181C HIV-1 RT binding pockets. The results derived from docking analysis show that hydrogen bonding interactions, pi-pi interactions, hydrogen-pi interactions and Van der waals interactions are important for binding of DAPYs. In order to elucidate the structural requirements of DAPYs, 3d-QSAR models using CoMFA and CoMSIA based on the docking alignment. Moreover, 2D-QSAR using HQSAR approach was applied. The models exhibited statistically significant results for CoMFA, CoMSIA and HQSAR on WT and K103N/Y181C HIV-1 RT inhibition as the q2 are higher than 0.6. A graphic interpretation obtained from the best QSAR models provide structural requirements thus offering guidelines for the synthesis of novel and more potent HIV-1 RT inhibitors in a series of DAPY analogs. To investigate the crucial interactions and binding energy of highly potent DAYPs in WT and K103N/Y181 C HIV-1 RT binding pockets, quantum chemical calculations, based on ONIOM2 (M06-2X/6-31G(d,p)/PM3MM) methods were performed. The obtained results indicate that interactions between TMC278 and highly potent DAPY and Lys101, Lys103, Tyrl181 of p66 domain and Glu138 of the p51 palm domain were found to be most favorable in WT binding pocket. In K103N/Y181C HIV-1 RT binding pocket, the mutations of Lys103, Tyr181 of p66 domain to Asn103 and Cys181 cause the loss of the interctions energies both of TMC278 and highly potent DAPY. Based on the binding energy, the mutations of amino acid residues are decreasing the stability of DAPY in HIV-1 RT binding pocket. The structural basis derived from molecular docking, QSAR and ONIOM2 approaches provide a gainful guideline to design highly potent DAPYs for WT and K103N/Y181C HIV-1 RT inhibitions. Based on the integrated results, 19 and 7 newly designed compounds for WT and K103N/Y181C HIV-1 RT inhibitions, respectively showing the higher inhibitory activities as compared with the parent compounds have been proposed in this study.