Document Type
Preprint
Publication Date
4-5-2022
Journal / Book Title
Chembiochem
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.
DOI
10.1002/cbic.202100704
Montclair State University Digital Commons Citation
Eck, Tyler; Laureano de Souza, Mariana; Delvillar, Melvin; Ashraf, Kutub; Yadav Bheemanaboina, Rammohan R.; Chakrasali, Ramappa; Kreiss, Tamara; Siekierka, John J.; Rotella, David P.; Bhanot, Purnima; and Goodey, Nina M., "Characterization of Competitive Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase**" (2022). Department of Chemistry and Biochemistry Faculty Scholarship and Creative Works. 617.
https://digitalcommons.montclair.edu/chem-biochem-facpubs/617
Rights
Author manuscript; available in PMC 2023 April 05. Published in final edited form as: Chembiochem. 2022 April 05; 23(7): e202100704. doi:10.1002/cbic.202100704.
Comments
Published in final edited form as: Chembiochem. 2022 April 05; 23(7): e202100704. doi:10.1002/cbic.202100704.