Refined models of New Delhi metallo-beta-lactamase-1 with inhibitors: an QM/MM modeling study |
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Authors: | Yeng-Tseng Wang Tian-Lu Cheng |
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Institution: | 1. Department of Biochemistry, College of Medicine, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan, P.R. China;2. Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan, P.R. China;3. Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan, P.R. China |
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Abstract: | New Delhi metallo-beta-lactamase 1 (NDM-1) has been identified as a potential target for the treatment of multi-drug resistance bacterial infections. We used molecular docking, normal MD, SIE, QM/MM MD simulations, QM/MM GBSA binding free energy, and QM/MM GBSA alanine-scanning mutagenesis techniques to investigate interactions of the NDM-1 with 11 inhibitors (Tigecycline, BAL30072, D-captopril, Penicillin G, Ampicillin, Carbenicillin, Cephalexin, Cefaclor, Nitrocefin, Meropenem, and Imipenem). From our normal MD and QM/MM simulations, the correlation coefficients between the predicted binding free energies and experimental values are .88 and .93, respectively. Then simulations, which combined QM/MM/GBSA and alanine-scanning mutagenesis techniques, were performed and our results show that two residues (Lys211 and His250) have the strongest impact on the binding affinities of the 11 NDM-1/inhibitors. Therefore, our approach theoretically suggests that the two residues (Lys211 and His250) are responsible for the selectivity of NDM-1 associated inhibitors. |
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Keywords: | quantum mechanics/molecular mechanics molecular dynamics New Delhi metallo-beta-lactamase 1 muti-drugs resistance alanine-scanning mutagenesis molecular docking |
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