Characterization of Competitive Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase

Autor:	Tyler Eck, Mariana Laureano de Souza, Melvin Delvillar, Kutub Ashraf, Rammohan R. Yadav Bheemanaboina, Ramappa Chakrasali, Tamara Kreiss, John J. Siekierka, David P. Rotella, Purnima Bhanot, Nina M. Goodey
Rok vydání:	2022
Předmět:	Antimalarials Binding Sites Protein Domains Organic Chemistry Plasmodium falciparum Cyclic GMP-Dependent Protein Kinases Molecular Medicine Humans Molecular Biology Biochemistry Protein Kinase Inhibitors Article
Zdroj:	Chembiochem
ISSN:	1439-7633
Popis:	P. falciparum cGMP-dependent protein kinase (PfPKG) is an enticing anti-malarial drug target. Novel chemotypes are needed because existing inhibitors have safety issues that may prevent further development. This work demonstrates isoxazole-based compounds are potent ATP competitive inhibitors of PfPKG and discloses a new analog in this series. Isoxazoles 3 and 5 had K(i) values that are comparable to a known standard, 4-[2-(4-fluorophenyl)-5-(1-methylpiperidine-4-yl)-1H pyrrol-3-yl] pyridine. They also exhibited excellent selectivity for PfPKG over the human ortholog and the gatekeeper mutant T618Q PfPKG, which mimics the less accessible binding site of the human ortholog. The human ortholog’s larger binding site volume was predicted to explain the selectivity of the inhibitors for the P. falciparum enzyme.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::93cbf8dfbddf28ef59a5017fb94c15ac https://pubmed.ncbi.nlm.nih.gov/35044710 Zobrazit plný text záznamu Plný text