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Divide-and-conquer-based quantum chemical study for interaction between HIV-1 reverse transcriptase and MK-4965 inhibitor

Authors

  • Patchreenart Saparpakorn,

    1. Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Tokyo 169-8555, Japan
    2. Department of Chemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand
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  • Masato Kobayashi,

    1. Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Tokyo 169-8555, Japan
    2. Department of Theoretical and Computational Molecular Science, Institute for Molecular Science, Okazaki 444-8585, Japan
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  • Supa Hannongbua,

    1. Department of Chemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand
    2. Center of Nanotechnology KU, Kasetsart University, Bangkok 10900, Thailand
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  • Hiromi Nakai

    Corresponding author
    1. Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Tokyo 169-8555, Japan
    2. Research Institute for Science and Engineering, Waseda University, Tokyo 169-8555, Japan
    3. CREST, Japan Science and Technology Agency, Tokyo 102-0075, Japan
    • Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Tokyo 169-8555, Japan
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Abstract

MK-4965, 3-{5-[(6-Amino-1H-pyrazolo[3,4-b]pyridine-3-yl)methoxy]-2-chlorophenoxy}-5-chloro-benzonitrile, is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) revealing high levels of potency against wild-type (WT) the human immunodeficiency virus type-1 (HIV-1) and some important mutants. The divide-and-conquer (DC) based Hartree–Fock (HF) and second-order Møller–Plesset perturbation theory (MP2) calculations were performed for the binding modes of MK-4965 in the reverse transcriptase (RT) of the WT HIV-1 and a mutant Y181C, 181 tyrosine mutated by cysteine. The binding pockets of MK-4965 consisting of 19 residues are selected for the study. Numerical assessments confirmed the efficiency and accuracy of the DC-MP2 method in comparison with the conventional MP2 one. Subsystem interaction energies obtained by the DC-MP2 calculations clarified the key parts of the binding between MK-4965 and HIV-1: hydrogen bonding with 102 lysine, which is apart from mutated 181 residue. The present information can give a helpful guide for the future inhibitor design. © 2012 Wiley Periodicals, Inc.

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