1. A chalcone derivative binds a putative allosteric site of YopH: Inhibition of a virulence factor of Yersinia.
- Author
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de Souza ACA, Mori M, Sens L, Rocha RF, Tizziani T, de Souza LFS, Domeneghini Chiaradia-Delatorre L, Botta M, Nunes RJ, Terenzi H, and Menegatti ACO
- Subjects
- Allosteric Site drug effects, Bacterial Outer Membrane Proteins metabolism, Chalcone chemical synthesis, Chalcone chemistry, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Molecular Structure, Protein Tyrosine Phosphatases metabolism, Structure-Activity Relationship, Virulence Factors metabolism, Bacterial Outer Membrane Proteins antagonists & inhibitors, Chalcone pharmacology, Enzyme Inhibitors pharmacology, Protein Tyrosine Phosphatases antagonists & inhibitors, Virulence Factors antagonists & inhibitors
- 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
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