Inhibition of pseudolysin and thermolysin by hydroxamate-based MMP inhibitors

Eur J Med Chem. 2015 Jan 7:89:340-8. doi: 10.1016/j.ejmech.2014.10.009. Epub 2014 Oct 18.

Abstract

In the present study, we have investigated the inhibition of thermolysin and pseudolysin by a series of compounds previously identified as matrix metalloproteinase (MMP) inhibitors using experimental binding studies and theoretical calculations. The experimental studies showed that some of the compounds were able to inhibit thermolysin and pseudolysin in the low μM range. The studies revealed that, in general, the compounds bound in the order MMPs > pseudolysin > thermolysin, and the strongest pseudolysin and thermolysin binders were compounds 8-12. Furthermore, compounds 8 and 9 were unique in that they bound much stronger to the two bacterial enzymes than to the MMPs. The docking calculations suggested that the phenyl group of the strongest binders (compounds 8 and 9) occupy the S2(')-subpocket, while a second ring system occupy the S1-subpocket in both thermolysin and pseudolysin. When the compounds possess two ring systems, the largest and most electron rich ring system seems to occupy the S1-subpocket.

Keywords: Docking and scoring; Enzyme inhibitors; Matrix metalloproteinase; Pseudolysin; Thermolysin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / chemistry
  • Drug Design
  • Hydroxamic Acids / chemistry*
  • Ligands
  • Matrix Metalloproteinase Inhibitors / chemistry*
  • Matrix Metalloproteinase Inhibitors / pharmacology
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Molecular Sequence Data
  • Molecular Structure
  • Protein Binding
  • Sequence Homology
  • Substrate Specificity
  • Thermolysin / antagonists & inhibitors*
  • Thermolysin / chemistry

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Hydroxamic Acids
  • Ligands
  • Matrix Metalloproteinase Inhibitors
  • Thermolysin