Abstract
Calcium-dependent protein kinase-1 (CDPK1) from Cryptosporidium parvum (CpCDPK1) and Toxoplasma gondii (TgCDPK1) have become attractive targets for discovering selective inhibitors to combat infections caused by these protozoa. We used structure-based design to improve a series of benzoylbenzimidazole-based compounds in terms of solubility, selectivity, and potency against CpCDPK1 and TgCDPK1. The best inhibitors show inhibitory potencies below 50 nM and selectivity well above 200-fold over two human kinases with small gatekeeper residues.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Benzimidazoles / chemical synthesis
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Benzimidazoles / chemistry*
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Benzimidazoles / metabolism
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Cryptosporidium parvum / enzymology*
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Drug Design
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Humans
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Protein Binding
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / metabolism
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Protein Kinases / chemistry*
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Protein Kinases / metabolism
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Proto-Oncogene Proteins c-abl / antagonists & inhibitors
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Proto-Oncogene Proteins c-abl / metabolism
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Protozoan Proteins / antagonists & inhibitors*
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Protozoan Proteins / metabolism
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Solubility
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Structure-Activity Relationship
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Toxoplasma / enzymology*
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src-Family Kinases / antagonists & inhibitors
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src-Family Kinases / metabolism
Substances
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Benzimidazoles
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Protein Kinase Inhibitors
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Protozoan Proteins
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benzimidazole
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Protein Kinases
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calcium-dependent protein kinase
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Proto-Oncogene Proteins c-abl
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src-Family Kinases