Discovery of potential inhibitors against New Delhi metallo-β-lactamase-1 from natural compounds: in silico-based methods

Sci Rep. 2021 Jan 27;11(1):2390. doi: 10.1038/s41598-021-82009-6.


New Delhi metallo-β-lactamase variants and different types of metallo-β-lactamases have attracted enormous consideration for hydrolyzing almost all β-lactam antibiotics, which leads to multi drug resistance bacteria. Metallo-β-lactamases genes have disseminated in hospitals and all parts of the world and became a public health concern. There is no inhibitor for New Delhi metallo-β-lactamase-1 and other metallo-β-lactamases classes, so metallo-β-lactamases inhibitor drugs became an urgent need. In this study, multi-steps virtual screening was done over the NPASS database with 35,032 natural compounds. At first Captopril was extracted from 4EXS PDB code and use as a template for the first structural screening and 500 compounds obtained as hit compounds by molecular docking. Then the best ligand, i.e. NPC120633 was used as templet and 800 similar compounds were obtained. As a final point, ten compounds i.e. NPC171932, NPC100251, NPC18185, NPC98583, NPC112380, NPC471403, NPC471404, NPC472454, NPC473010 and NPC300657 had proper docking scores, and a 50 ns molecular dynamics simulation was performed for calculation binding free energy of each compound with New Delhi metallo-β-lactamase. Protein sequence alignment, 3D conformational alignment, pharmacophore modeling on all New Delhi metallo-β-lactamase variants and all types of metallo-β-lactamases were done. Quantum chemical perspective based on the fragment molecular orbital (FMO) method was performed to discover conserved and crucial residues in the catalytic activity of metallo-β-lactamases. These residues had similar 3D coordinates of spatial location in the 3D conformational alignment. So it is posibble that all types of metallo-β-lactamases can inhibit by these ten compounds. Therefore, these compounds were proper to mostly inhibit all metallo-β-lactamases in experimental studies.

MeSH terms

  • Binding Sites
  • Biological Products / chemistry*
  • Biological Products / pharmacology
  • Computational Biology / methods
  • Ligands
  • Molecular Conformation
  • Molecular Docking Simulation*
  • Molecular Dynamics Simulation*
  • Molecular Structure
  • Protein Binding
  • Structure-Activity Relationship
  • Thermodynamics
  • beta-Lactamase Inhibitors / chemistry*
  • beta-Lactamase Inhibitors / pharmacology
  • beta-Lactamases / chemistry*


  • Biological Products
  • Ligands
  • beta-Lactamase Inhibitors
  • beta-Lactamases
  • beta-lactamase NDM-1