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Comparison of the Molecular Dynamics and Calculated Binding Free Energies for Nine FDA-Approved HIV-1 PR Drugs Against Subtype B and C-SA HIV PR

Authors

  • Shaimaa M. Ahmed,

    1. School of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa
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  • Hendrik G. Kruger,

    Corresponding author
    1. Center of catalysis and peptide synthesis, School of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa
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  • Thirumala Govender,

    1. School of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa
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  • Glenn E. M. Maguire,

    1. Center of catalysis and peptide synthesis, School of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa
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  • Yasien Sayed,

    1. Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand, Wits 2050, South Africa
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  • Mahmoud A. A. Ibrahim,

    1. School of Chemistry, University of Manchester, Oxford Road, Manchester M139PL, UK
    2. Chemistry Department, Faculty of Science, Minia University, Minia 61519, Egypt
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  • Previn Naicker,

    1. Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand, Wits 2050, South Africa
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  • Mahmoud E. S. Soliman

    Corresponding author
    1. School of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa
    2. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
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Corresponding authors: Mahmoud E. S. Soliman, soliman@ukzn.ac.za and Hendrik G. Kruger, kruger@ukzn.ac.za

Abstract

We report the first account of a comparative analysis of the binding affinities of nine FDA-approved drugs against subtype B as well as the South African subtype C HIV PR (C-SA). A standardized protocol was used to generate the inhibitor/C-SA PR complexes with the relative positions of the inhibitors taken from the corresponding X-ray structures for subtype B complexes. The dynamics and stability of these complexes were investigated using molecular dynamics calculations. Average relative binding free energies for these inhibitors were calculated from the molecular dynamics simulation using the molecular mechanics generalized Born surface area method. The calculated energies followed a similar trend to the reported experimental binding free energies. Postdynamic hydrogen bonding and electrostatic interaction analysis of the inhibitors with both subtypes reveal similar interactions. Most inhibitors show slightly weaker binding affinities for C-SA PR. Molecular dynamics studies demonstrated increased flap movement for C-SA PR, which can perhaps explain the weaker affinities. This study serves as a standardized platform for optimizing the design of future more potent HIV C-SA PR inhibitors.

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