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

Chembiochem. 2022 Apr 5;23(7):e202100704. doi: 10.1002/cbic.202100704. Epub 2022 Feb 23.

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.

MeSH terms

  • Antimalarials* / pharmacology
  • Binding Sites
  • Cyclic GMP-Dependent Protein Kinases* / antagonists & inhibitors
  • Cyclic GMP-Dependent Protein Kinases* / chemistry
  • Humans
  • Plasmodium falciparum* / drug effects
  • Protein Domains
  • Protein Kinase Inhibitors* / pharmacology

Substances

  • Antimalarials
  • Protein Kinase Inhibitors
  • Cyclic GMP-Dependent Protein Kinases