RESUMO

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.

Assuntos

Proteínas da Membrana Bacteriana Externa/antagonistas & inibidores , Chalcona/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Fatores de Virulência/antagonistas & inibidores , Sítio Alostérico/efeitos dos fármacos , Proteínas da Membrana Bacteriana Externa/metabolismo , Chalcona/síntese química , Chalcona/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrutura Molecular , Proteínas Tirosina Fosfatases/metabolismo , Relação Estrutura-Atividade , Fatores de Virulência/metabolismo