RESUMEN

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.

Asunto(s)

Proteínas de la Membrana Bacteriana Externa/antagonistas & inhibidores , Chalcona/farmacología , Inhibidores Enzimáticos/farmacología , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Factores de Virulencia/antagonistas & inhibidores , Sitio Alostérico/efectos de los fármacos , Proteínas de la Membrana Bacteriana Externa/metabolismo , Chalcona/síntesis química , Chalcona/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Estructura Molecular , Proteínas Tirosina Fosfatasas/metabolismo , Relación Estructura-Actividad , Factores de Virulencia/metabolismo