Characterization of Competitive Inhibitors of Plasmodium falciparum cGMP‐Dependent Protein Kinase**
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 23, 2022
- Source ID
- 10.1002/cbic.202100704
Entities
People
- David P. Rotella
- John J. Siekierka
- Kutub Ashraf
- Mariana Laureano de Souza
- Melvin Delvillar
- Nina M Goodey
- Purnima Bhanot
- Ramappa Chakrasali
- Rammohan R. Yadav Bheemanaboina
- Tamara Kreiss
- Tyler Eck
Organizations
- Montclair State University
- National Institutes of Health
- Rutgers University
- United States Department of Defense