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A study of the interaction between HIV-1 protease and C 2-symmetric inhibitors by computational methods

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Abstract

The human immunodeficiency virus type 1 protease (HIV-1 PR) is a major target for the design of anti-AIDS (acquired immune deficiency syndrome) drugs. Some C 2-symmetric inhibitors have been designed for the C 2-symmetric binding pocket of HIV-1PR. The crystallographic structures reveal that the binding modes are not C 2-symmetric for C 2- symmetric inhibitors binding to PR. In this work, four molecular dynamics (MD) simulations were performed to investigate the binding modes between four C 2-symmetric inhibitors (6 AD, 6AG, 6FD and 6FG) and PR, as well as the stabilities of these inhibitors in the binding pocket. Analysis of the hydrophobic surface of the binding pocket shows that it is necessary to add a polar group to the P1 (benzyl) and P2 (phenyl) groups of the inhibitor 6AD. Analysis of the hydrogen bonds formed between inhibitors and residues (Asp25/Asp25′, Ile50/Ile50′) indicates that the steric structures of the inhibitors are not suitable for the binding pocket. The two increased polar groups of trifluoromethyl and formamido meet the needs of the binding pocket for polar molecules. The inhibitor with both these groups (6FG) has stronger stability than the other three inhibitors, which have only one (6AG and 6FD) or none (6AD) of these groups. The ranking of binding free energies calculated by molecular mechanics-generalized born surface area (MM-GBSA) method agrees well with the experimental data. It is expected that this study will provide theoretical guidance for the design of anti-AIDS drugs targeting HIV-1PR.

Left Inhibitor 6AD in the binding pocket of human immunodeficiency virus type 1 protease. Right Differences of free energies for trifluoromethyl and formaminde

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Acknowledgments

This work was partially supported by funding from the National Natural Science Foundation of China (61271378 and 11274206), the Natural Science Foundation of Shandong Province (ZR2013AM014 and ZR2012CL09) and A Project of Shandong Province Higher Educational Science and Technology Program (J14LJ05).

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Authors and Affiliations

  1. College of Science, Shandong Jianzhu University, Jinan, 250101, China

    Shuhua Shi

  2. Shandong Provincial Key Laboratory of Functional Macromolecular Biophysics, College of Physics and Electronic Engineering, Dezhou University, Dezhou, 253023, China

    Guodong Hu, Xiumei Zhang & Jihua Wang

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  1. Shuhua Shi
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  2. Guodong Hu
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  3. Xiumei Zhang
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  4. Jihua Wang
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Correspondence to Guodong Hu.

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Shi, S., Hu, G., Zhang, X. et al. A study of the interaction between HIV-1 protease and C 2-symmetric inhibitors by computational methods. J Mol Model 20, 2369 (2014). https://doi.org/10.1007/s00894-014-2369-3

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  • DOI: https://doi.org/10.1007/s00894-014-2369-3

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