High-Throughput Virtual Screening, Molecular Dynamics Simulation, and Enzyme Kinetics Identified ZINC84525623 as a Potential Inhibitor of NDM-1

Abstract

The bacteria expressing New Delhi Metallo-β-lactamase-1 (NDM-1) can hydrolyze all β-lactam antibiotics including carbapenems, causing multi-drug resistance. The worldwide emergence and dissemination of gene blaNDM-1 (produces NDM-1) in hospital and community settings, rising problems for public health. Indeed, there is an urgent need for NDM-1 inhibitors to manage antibiotic resistance. Here, we have identified novel non-β-lactam ring-containing inhibitors of NDM-1 by applying a high-throughput virtual screening of lead-like subset of ZINC database. The screened compounds were followed for the molecular docking, the molecular dynamics simulation, and then enzyme kinetics assessment. The adopted screening procedure funnels out five novel inhibitors of NDM-1 including ZINC10936382, ZINC30479078, ZINC41493045, ZINC7424911, and ZINC84525623. The molecular mechanics-generalized born surface area and molecular dynamics (MD) simulation showed that ZINC84525623 formed the most stable complex with NDM-1. Furthermore, analyses of the binding pose after MD simulation revealed that ZINC84525623 formed two hydrogen bonds (electrostatic and hydrophobic interaction) with key amino acid residues of the NDM-1 active site. The docking binding free energy and docking binding constant for the ZINC84525623 and NDM-1 interaction were estimated to be −11.234 kcal/mol, and 1.74 × 108 M−1 respectively. Steady-state enzyme kinetics in the presence of ZINC84525623 show the decreased catalytic efficiency (i.e., kcat/Km) of NDM-1 on various antibiotics. The findings of this study would be helpful in identifying novel inhibitors against other β-lactamases from a pool of large databases. Furthermore, the identified inhibitor (ZINC84525623) could be developed as efficient drug candidates.

Insight of the Interaction between 2,4-thiazolidinedione and Human Serum Albumin: A Spectroscopic, Thermodynamic and Molecular Docking Study

“…Molecular dynamics simulation was performed using Desmond (Schrödinger, LLC, New York, NY, USA) for 50 ns using NTP ensemble at 300 K temperature and 1 bar atmospheric pressure as described earlier [53,54]. The docked HSA-2,4-TZD complex was considered as the initial conformation of the complex for the simulation.…”

Dieckol and Its Derivatives as Potential Inhibitors of SARS-CoV-2 Spike Protein (UK Strain: VUI 202012/01): A Computational Study

“…Prime calculates MM-GBSA using the relative binding affinity of protein–ligand without considering any simulation process. Furthermore, previous reports suggest a disagreement between docking Δ G and MM-GBSA Δ G bind determined using Prime module [ 29 , 30 , 31 ]. Many ligands have been shown to bind the RBD of Spike protein with an estimated value of Δ G bind in the range of −21.45 to −54.11 kcal/mol, which is close to our estimated value [ 32 , 33 ].…”

Specific NDM-1 Inhibitor of Isoliquiritin Enhances the Activity of Meropenem against NDM-1-positive Enterobacteriaceae in vitro

“…However, it has no obvious effect on NDM-1 variants and other class B metal β-lactamases, which may be because the binding site of the isoliquiritigenin is near to the site of NDM-1 mutates to NDM-5. Therefore, our study provides a new strategy for the design of specific inhibitors for specific enzymes, which could significantly improve the synergistic effect with carbapenemase, and needed to combine with biochemistry for chemical structure modification [8,9].…”

“…To date, NDM-1 has been detected in different Gram-negative bacteria such as E. coli and K. pneumoniae and has spread throughout the world [7]. NDM-1 is one of the most important metallo-β-lactamases and belongs to class B1 which has the most clinical relevance [8]. Thus, novel and effective therapeutics to combat serious clinical infections caused by NDM-1-producing Gram-negative bacteria, such as Enterobacteriaceae and Acinetobacter baumannii, are urgently needed.…”