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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Colloids
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Cysteine Endopeptidases / chemistry
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Cysteine Proteinase Inhibitors / chemical synthesis
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Cysteine Proteinase Inhibitors / chemistry*
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Cysteine Proteinase Inhibitors / pharmacology
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Databases, Factual
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Glycolates / chemical synthesis
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Glycolates / chemistry
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Glycolates / pharmacology
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Models, Molecular
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Oxadiazoles / chemical synthesis
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Oxadiazoles / chemistry
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Oxadiazoles / pharmacology
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Parasitic Sensitivity Tests
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Protozoan Proteins / antagonists & inhibitors*
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Protozoan Proteins / chemistry
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Structure-Activity Relationship
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Trypanocidal Agents / chemical synthesis
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Trypanocidal Agents / chemistry*
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Trypanocidal Agents / pharmacology
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Trypanosoma cruzi / drug effects*
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Trypanosoma cruzi / enzymology
Substances
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Colloids
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Cysteine Proteinase Inhibitors
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Glycolates
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Oxadiazoles
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Protozoan Proteins
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Trypanocidal Agents
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Cysteine Endopeptidases
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cruzain, Trypanosoma cruzi