Molecular Modeling and Docking Studies of 2,4,5-Trisubstituted Pyrimidines as HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

Abstract

Human immunodeficiency virus (HIV) reverse transcriptase (RT) works in the life cycle of HIV and is one of the key targets for anti-HIV-1 drug development. Recently, a novel series of diarylpyrimidine derivatives (DAPYs) have been reported as potent HIV-1 non-nucleoside RT inhibitors (NNRTIs), and they exhibit potent antiviral activity. Here we explored the binding interaction patterns of a set of 2,4,5-trisubstituted pyrimidine derivatives using molecular docking, three-dimensional quantitative structure–activity relationships (3D-QSAR), and molecular dynamics (MD) simulations. Molecular docking for exploring the mechanism of action of small molecule ligands with receptor proteins. Comparative molecular field (CoMFA q² = 0.828, r² = 0.988, r²_pred = 0.981) and comparative molecular similarity index (CoMSIA q² = 0.859, r² = 0.968, r²_pred = 0.980) were performed to build stable and reliable 3D-QSAR models. The contour plots revealed the relationship between structural features and inhibitory activities. Based on the molecular docking analysis and contour maps, some novel compounds with higher predicted activities were designed and further MD simulations and bind free energy calculations were performed. Our models results may provide an essential reference for the design and development of effective novel HIV-1 NNRTIs.

Keywords:

• HIV-1 NNRTIs
• molecular docking
• 3D-QSAR
• molecular dynamics

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the financial support of the National Natural Science Foundation of China [NO. 81172918, 51707122], Shanghai Municipal Education Commission [NO. SLG14033], and the open project program of Hubei Key Laboratory of Drug Synthesis and Optimization, Jing Chu University of Technology [NO. OPP2014ZD01].