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Divergent modes of enzyme inhibition in a homologous structure-activity series.

ABSTRACT: A docking screen identified reversible, noncovalent inhibitors (e.g., 1) of the parasite cysteine protease cruzain. Chemical optimization of 1 led to a series of oxadiazoles possessing interpretable SAR and potencies as much as 500-fold greater than 1. Detailed investigation of the SAR series subsequently revealed that many members of the oxadiazole class (and surprisingly also 1) act via divergent modes of inhibition (competitive or via colloidal aggregation) depending on the assay conditions employed.

SUBMITTER: Ferreira RS

PROVIDER: S-EPMC3760508 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Divergent modes of enzyme inhibition in a homologous structure-activity series.

Ferreira Rafaela S RS Bryant Clifford C Ang Kenny K H KK McKerrow James H JH Shoichet Brian K BK Renslo Adam R AR

Journal of medicinal chemistry 20090801 16

A docking screen identified reversible, noncovalent inhibitors (e.g., 1) of the parasite cysteine protease cruzain. Chemical optimization of 1 led to a series of oxadiazoles possessing interpretable SAR and potencies as much as 500-fold greater than 1. Detailed investigation of the SAR series subsequently revealed that many members of the oxadiazole class (and surprisingly also 1) act via divergent modes of inhibition (competitive or via colloidal aggregation) depending on the assay conditions e ...[more]

PMID: 19637873

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