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Novel theoretically designed HIV-1 non-nucleoside reverse transcriptase inhibitors derived from nevirapine

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Abstract

A common problem with non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1 is the emergence of mutations in the HIV-1 RT, in particular Lys103 → Asn (K103N) and Tyr181 → Cys (Y181C), which lead to resistance to this entire class of inhibitors. In this study, we theoretically designed two new non-nucleoside HIV-1 RT inhibitors, Mnev-1 and Mnev-2, derived from nevirapine, in order to reduce the resistance caused by those HIV-1 RT mutations. The binding modes of Mnev-1 and Mnev-2 with the wild-type HIV-1 RT and its mutants (K103N and Y181C) were suggested by molecular docking followed by 20-ns molecular dynamics (MD) simulations in explicit water of those binding complexes (HIV-1 RTs with the new inhibitors). A molecular mechanics/generalized Born surface area (MM/GBSA) calculation was carried out for multiple snapshots extracted from the MD trajectory to estimate the binding free energy. The results of the calculations show that each of the new inhibitors forms a stable hydrogen bond with His235 during the MD simulations, leading to tighter binding of the new inhibitors with their targets. In addition, the repulsive interaction with Cys181 in the Y181C–nevirapine complex is not present in the novel inhibitors. The binding affinities predicted using the MM/GBSA calculations indicate that the new inhibitors could be effective at bypassing the drug resistance of these HIV-1 RT mutants.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (grant nos. 10974054, 20933002 and 21303057) and Shanghai PuJiang program (09PJ1404000). X.H. is also supported by the Specialized Research Fund for the Doctoral Program of Higher Education (grant no. 20130076120019) and the Fundamental Research Funds for the Central Universities. We thank the Supercomputer Center of East China Normal University for providing us with computational time.

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Authors and Affiliations

  1. State Key Laboratory of Precision Spectroscopy and Department of Physics, Institute of Theoretical and Computational Science, East China Normal University, Shanghai, 200062, China

    Jinfeng Liu, Xiao He & John Z. H. Zhang

  2. NYU-ECNU Center for Computational Chemistry at NYU Shanghai, Shanghai, 200062, China

    Xiao He & John Z. H. Zhang

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  1. Jinfeng Liu
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  2. Xiao He
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Correspondence to Xiao He.

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Liu, J., He, X. & Zhang, J.Z.H. Novel theoretically designed HIV-1 non-nucleoside reverse transcriptase inhibitors derived from nevirapine. J Mol Model 20, 2451 (2014). https://doi.org/10.1007/s00894-014-2451-x

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