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

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) is an enticing antimalarial 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 analogue in this series. Isoxazoles 3 and 5 had Ki 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 orthologue and the gatekeeper mutant T618Q PfPKG, which mimics the less accessible binding site of the human orthologue. The human orthologue's larger binding site volume is predicted to explain the selectivity of the inhibitors for the P. falciparum enzyme.

Original languageEnglish
Article numbere202100704
JournalChemBioChem
Volume23
Issue number7
DOIs
StatePublished - 5 Apr 2022

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