2. Academic Validation
  3. Structure-Activity Relationship of a Pyrrole Based Series of PfPKG Inhibitors as Anti-Malarials

Structure-Activity Relationship of a Pyrrole Based Series of PfPKG Inhibitors as Anti-Malarials

  • J Med Chem. 2024 Feb 19. doi: 10.1021/acs.jmedchem.3c01795.
John A Gilleran 1,  Kutub Ashraf 2,  Melvin Delvillar 2,  Tyler Eck 3,  Raheel Fondekar 1 4,  Edward B Miller 5,  Ashley Hutchinson 6,  Aiping Dong 6,  Alma Seitova 6,  Mariana Laureano De Souza 2,  David Augeri 1 5,  Levon Halabelian 6 7,  John Siekierka 3,  David P Rotella 3,  John Gordon 8,  Wayne E Childers 8,  Mark C Grier 1,  Bart L Staker 9 10,  Jacques Y Roberge 1,  Purnima Bhanot 2
Affiliations

Affiliations

  • 1 Rutgers Molecular Design and Synthesis Core, Office for Research, Rutgers University, 610 Taylor Road, Piscataway, New Jersey 08854, United States.
  • 2 Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, 225 Warren Street, Newark, New Jersey 07103, United States.
  • 3 Department of Chemistry and Biochemistry and Sokol Institute of Pharmaceutical Life Sciences, Montclair State University, Montclair, New Jersey 07043, United States.
  • 4 Rutgers School of Pharmacy, 160 Frelinghuysen Road, Piscataway, New Jersey 08854, United States.
  • 5 Schrödinger, Inc., 1540 Broadway, 24th Floor, New York, New York 10036, United States.
  • 6 Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • 7 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
  • 8 Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, Pennsylvania 19140, United States.
  • 9 Seattle Structural Genomics Center for Infectious Disease, Seattle, Washington 98109, United States.
  • 10 Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington 98109, United States.
PMID: 38372781 DOI: 10.1021/acs.jmedchem.3c01795
Abstract

Controlling malaria requires new drugs against Plasmodium falciparum. The P. falciparum cGMP-dependent protein kinase (PfPKG) is a validated target whose inhibitors could block multiple steps of the parasite's life cycle. We defined the structure-activity relationship (SAR) of a pyrrole series for PfPKG inhibition. Key pharmacophores were modified to enable full exploration of chemical diversity and to gain knowledge about an ideal core scaffold. In vitro potency against recombinant PfPKG and human PKG were used to determine compound selectivity for the Parasite enzyme. P. berghei sporozoites and P. falciparum asexual blood stages were used to assay multistage antiparasitic activity. Cellular specificity of compounds was evaluated using transgenic parasites expressing PfPKG carrying a substituted "gatekeeper" residue. The structure of PfPKG bound to an inhibitor was solved, and modeling using this structure together with computational tools was utilized to understand SAR and establish a rational strategy for subsequent lead optimization.

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