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J Med Chem. 2009 Aug 27;52(16):5005-8. doi: 10.1021/jm9009229.

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

Author information

1
Small Molecule Discovery Center, Sandler Center for Basic Research in Parasitic Diseases, and Department of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th Street, San Francisco, CA 94158, USA.

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.

PMID:
19637873
PMCID:
PMC3760508
DOI:
10.1021/jm9009229
[Indexed for MEDLINE]
Free PMC Article

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