A chalcone derivative binds a putative allosteric site of YopH: Inhibition of a virulence factor of Yersinia

Bioorg Med Chem Lett. 2020 Aug 15;30(16):127350. doi: 10.1016/j.bmcl.2020.127350. Epub 2020 Jun 12.

Abstract

Identification of allosteric inhibitors of PTPs has attracted great interest as a new strategy to overcome the challenge of discover potent and selective molecules for therapeutic intervention. YopH is a virulence factor of the genus Yersinia, validated as an antimicrobial target. The finding of a second substrate binding site in YopH has revealed a putative allosteric site that could be further exploited. Novel chalcone compounds that inhibit PTPs activity were designed and synthesized. Compound 3j was the most potent inhibitor, interestingly, with different mechanisms of inhibition for the panel of enzymes evaluated. Further, our results showed that compound 3j is an irreversible non-competitive inhibitor of YopH that binds to a site different than the catalytic site, but close to the well-known second binding site of YopH.

Keywords: Allosteric site; Chicoric acid; Non-competitive inhibitor; PTP; Yersinia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site / drug effects
  • Bacterial Outer Membrane Proteins / antagonists & inhibitors*
  • Bacterial Outer Membrane Proteins / metabolism
  • Chalcone / chemical synthesis
  • Chalcone / chemistry
  • Chalcone / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Molecular Structure
  • Protein Tyrosine Phosphatases / antagonists & inhibitors*
  • Protein Tyrosine Phosphatases / metabolism
  • Structure-Activity Relationship
  • Virulence Factors / antagonists & inhibitors*
  • Virulence Factors / metabolism

Substances

  • Bacterial Outer Membrane Proteins
  • Enzyme Inhibitors
  • Virulence Factors
  • Chalcone
  • Protein Tyrosine Phosphatases
  • yopH protein, Yersinia