Discovery of novel new Delhi metallo-β-lactamases-1 inhibitors by multistep virtual screening.
The emergence of NDM-1 containing multi-antibiotic resistant "Superbugs" necessitates the needs of developing of novel NDM-1inhibitors. In this study, we report the discovery of novel NDM-1 inhibitors by multi-step virtual screening. From a 2,800,000 virtual drug-like compound library selected from the ZINC database, we generated a focused NDM-1 inhibitor library containing 298 compounds of which 44 chemical compounds were purchased and evaluated experimentally for their ability to inhibit NDM-1 in vitro. Three novel NDM-1 inhibitors with micromolar IC50 values were validated. The most potent inhibitor, VNI-41, inhibited NDM-1 with an IC50 of 29.6 ± 1.3 μM. Molecular dynamic simulation revealed that VNI-41 interacted extensively with the active site. In particular, the sulfonamide group of VNI-41 interacts directly with the metal ion Zn1 that is critical for the catalysis. These results demonstrate the feasibility of applying virtual screening methodologies in identifying novel inhibitors for NDM-1, a metallo-β-lactamase with a malleable active site and provide a mechanism base for rational design of NDM-1 inhibitors using sulfonamide as a functional scaffold.
School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.
Xuequan
X
Wang
School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.
Meiling
M
Lu
School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.
Yang
Y
Shi
School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.
Yu
Y
Ou
Department of Integrative Biology & Pharmacology, The University of Texas Health Science Center, Houston, United States of America.
Xiaodong
X
Cheng
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism; D001618:beta-Lactamases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D013449:Sulfonamides; C000604398:VNI-41 compound; D001618:beta-Lactamases; C552864:beta-lactamase NDM-1