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Divergent Modes of Enzyme Inhibition in a Homologous Structure−Activity Series

2009; American Chemical Society; Volume: 52; Issue: 16 Linguagem: Inglês

10.1021/jm9009229

1520-4804

Rafaela Salgado Ferreira, Clifford Bryant, Kenny K. H. Ang, James H. McKerrow, Brian K. Shoichet, Adam R. Renslo,

Synthesis and Reactivity of Heterocycles

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.