Structure–Activity Relationship of a Pyrrole Based Series of PfPKG Inhibitors as Anti-MalarialsClick to copy article linkArticle link copied!
- John A. GilleranJohn A. GilleranRutgers Molecular Design and Synthesis Core, Office for Research, Rutgers University, 610 Taylor Road, Piscataway, New Jersey 08854, United StatesMore by John A. Gilleran
- Kutub AshrafKutub AshrafDepartment of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, 225 Warren Street, Newark, New Jersey 07103, United StatesMore by Kutub Ashraf
- Melvin DelvillarMelvin DelvillarDepartment of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, 225 Warren Street, Newark, New Jersey 07103, United StatesMore by Melvin Delvillar
- Tyler EckTyler EckDepartment of Chemistry and Biochemistry and Sokol Institute of Pharmaceutical Life Sciences, Montclair State University, Montclair, New Jersey 07043, United StatesMore by Tyler Eck
- Raheel FondekarRaheel FondekarRutgers Molecular Design and Synthesis Core, Office for Research, Rutgers University, 610 Taylor Road, Piscataway, New Jersey 08854, United StatesRutgers School of Pharmacy, 160 Frelinghuysen Road, Piscataway, New Jersey 08854, United StatesMore by Raheel Fondekar
- Edward B. MillerEdward B. MillerSchrödinger, Inc., 1540 Broadway, 24th Floor, New York, New York 10036, United StatesMore by Edward B. Miller
- Ashley HutchinsonAshley HutchinsonStructural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, CanadaMore by Ashley Hutchinson
- Aiping DongAiping DongStructural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, CanadaMore by Aiping Dong
- Alma SeitovaAlma SeitovaStructural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, CanadaMore by Alma Seitova
- Mariana Laureano De SouzaMariana Laureano De SouzaDepartment of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, 225 Warren Street, Newark, New Jersey 07103, United StatesMore by Mariana Laureano De Souza
- David AugeriDavid AugeriRutgers Molecular Design and Synthesis Core, Office for Research, Rutgers University, 610 Taylor Road, Piscataway, New Jersey 08854, United StatesSchrödinger, Inc., 1540 Broadway, 24th Floor, New York, New York 10036, United StatesMore by David Augeri
- Levon HalabelianLevon HalabelianStructural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, CanadaDepartment of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, CanadaMore by Levon Halabelian
- John SiekierkaJohn SiekierkaDepartment of Chemistry and Biochemistry and Sokol Institute of Pharmaceutical Life Sciences, Montclair State University, Montclair, New Jersey 07043, United StatesMore by John Siekierka
- David P. RotellaDavid P. RotellaDepartment of Chemistry and Biochemistry and Sokol Institute of Pharmaceutical Life Sciences, Montclair State University, Montclair, New Jersey 07043, United StatesMore by David P. Rotella
- John GordonJohn GordonMoulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, Pennsylvania 19140, United StatesMore by John Gordon
- Wayne E. ChildersWayne E. ChildersMoulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, Pennsylvania 19140, United StatesMore by Wayne E. Childers
- Mark C. GrierMark C. GrierRutgers Molecular Design and Synthesis Core, Office for Research, Rutgers University, 610 Taylor Road, Piscataway, New Jersey 08854, United StatesMore by Mark C. Grier
- Bart L. StakerBart L. StakerSeattle Structural Genomics Center for Infectious Disease, Seattle, Washington 98109, United StatesCenter for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, Washington 98109, United StatesMore by Bart L. Staker
- Jacques Y. Roberge*Jacques Y. Roberge*E-mail: [email protected]Rutgers Molecular Design and Synthesis Core, Office for Research, Rutgers University, 610 Taylor Road, Piscataway, New Jersey 08854, United StatesMore by Jacques Y. Roberge
- Purnima Bhanot*Purnima Bhanot*E-mail: [email protected]Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, 225 Warren Street, Newark, New Jersey 07103, United StatesMore by Purnima Bhanot
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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