Refined models of New Delhi metallo-beta-lactamase-1 with inhibitors: an QM/MM modeling study.
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.
a Department of Biochemistry , College of Medicine, Kaohsiung Medical University , 100, Shih-Chuan 1st Road, Kaohsiung 80708 , Taiwan, P.R. China.|b Center for Biomarkers and Biotech Drugs , Kaohsiung Medical University , Kaohsiung , Taiwan, P.R. China.
Yeng-Tseng
YT
Wang
b Center for Biomarkers and Biotech Drugs , Kaohsiung Medical University , Kaohsiung , Taiwan, P.R. China.
Tian-Lu
TL
Cheng
D015195:Drug Design; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D001618:beta-Lactamases / Q000737:chemistry* / Q000235:genetics
D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases; C552864:beta-lactamase NDM-1
New Delhi metallo-beta-lactamase 1; alanine-scanning mutagenesis; molecular docking; muti-drugs resistance; quantum mechanics/molecular mechanics molecular dynamics