4YJN

Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii (TgCDPK1) in complex with inhibitor UW1639

Summary for 4YJN

• Entry DOI: 10.2210/pdb4yjn/pdb
• Related: 4ONA
• Descriptor: Calmodulin-domain protein kinase 1, 5-amino-1-tert-butyl-3-[2-(cyclobutyloxy)quinolin-6-yl]-1H-pyrazole-4-carboxamide (3 entities in total)
• Functional Keywords: serine/threonine protein kinase, transferase, calcium-binding, atp-binding, bumped kinase inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Toxoplasma gondii
• Total number of polymer chains: 1
• Total formula weight: 55606.37

Authors

Merritt, E.A. (deposition date: 2015-03-03, release date: 2015-11-25, Last modification date: 2023-09-27)

Primary citation

Huang, W.,Ojo, K.K.,Zhang, Z.,Rivas, K.,Vidadala, R.S.,Scheele, S.,DeRocher, A.E.,Choi, R.,Hulverson, M.A.,Barrett, L.K.,Bruzual, I.,Siddaramaiah, L.K.,Kerchner, K.M.,Kurnick, M.D.,Freiberg, G.M.,Kempf, D.,Hol, W.G.,Merritt, E.A.,Neckermann, G.,de Hostos, E.L.,Isoherranen, N.,Maly, D.J.,Parsons, M.,Doggett, J.S.,Van Voorhis, W.C.,Fan, E.
SAR Studies of 5-Aminopyrazole-4-carboxamide Analogues as Potent and Selective Inhibitors of Toxoplasma gondii CDPK1.
Acs Med.Chem.Lett., 6:1184-1189, 2015

PubMed Abstract: We previously discovered compounds based on a 5-aminopyrazole-4-carboxamide scaffold to be potent and selective inhibitors of CDPK1 from . The current work, through structure-activity relationship studies, led to the discovery of compounds ( and ) with improved characteristics over the starting inhibitor in terms of solubility, plasma exposure after oral administration in mice, or efficacy on parasite growth inhibition. Compounds and were further demonstrated to be more effective than in a mouse infection model and markedly reduced the amount of in the brain, spleen, and peritoneal fluid, and given at 20 mg/kg eliminated from the peritoneal fluid.

PubMed: 26693272
DOI: 10.1021/acsmedchemlett.5b00319

Experimental method

X-RAY DIFFRACTION (2.6 Å)