Benzoylbenzimidazole-based selective inhibitors targeting Cryptosporidium parvum and Toxoplasma gondii calcium-dependent protein kinase-1.
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.
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Zhongsheng
Z
Zhang
Kayode K
KK
Ojo
Steven M
SM
Johnson
Eric T
ET
Larson
Penqing
P
He
Jennifer A
JA
Geiger
Alejandro
A
Castellanos-Gonzalez
A Clinton
AC
White
Marilyn
M
Parsons
Ethan A
EA
Merritt
Dustin J
DJ
Maly
Christophe L M J
CL
Verlinde
Wesley C
WC
Van Voorhis
Erkang
E
Fan
D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D016785:Cryptosporidium parvum / Q000201:enzymology*; D015195:Drug Design; D006801:Humans; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000378:metabolism; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D014122:Toxoplasma / Q000201:enzymology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases
D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D016315:Proto-Oncogene Proteins c-abl; D015800:Protozoan Proteins; D019061:src-Family Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C031000:benzimidazole