8EM8

Co-crystal structure of the cGMP-dependent protein kinase PKG from Plasmodium falciparum in complex with RY-1-165

Summary for 8EM8

• Entry DOI: 10.2210/pdb8em8/pdb
• Descriptor: cGMP-dependent protein kinase, unidentified peptide fragment, [(3R)-3-{[(4M)-4-(4-cyclopropyl-2-phenyl-1H-imidazol-1-yl)pyrimidin-2-yl]amino}pyrrolidin-1-yl](1,3-thiazol-2-yl)methanone, ... (5 entities in total)
• Functional Keywords: sgc, cgmp-kinase, inhibitor, structural genomics, structural genomics consortium, transferase
• Biological source: Plasmodium falciparum (isolate 3D7); More
• Total number of polymer chains: 2
• Total formula weight: 98630.55

Authors

Hutchinson, A.,Dong, A.,Seitova, A.,Bhanot, P.,Arrowsmith, C.H.,Edwards, A.M.,Halabelian, L.,Structural Genomics Consortium (SGC) (deposition date: 2022-09-27, release date: 2022-11-02, Last modification date: 2024-08-07)

Primary citation

Gilleran, J.A.,Ashraf, K.,Delvillar, M.,Eck, T.,Fondekar, R.,Miller, E.B.,Hutchinson, A.,Dong, A.,Seitova, A.,De Souza, M.L.,Augeri, D.,Halabelian, L.,Siekierka, J.,Rotella, D.P.,Gordon, J.,Childers, W.E.,Grier, M.C.,Staker, B.L.,Roberge, J.Y.,Bhanot, P.
Structure-Activity Relationship of a Pyrrole Based Series of PfPKG Inhibitors as Anti-Malarials.
J.Med.Chem., 67:3467-3503, 2024

PubMed Abstract: Controlling malaria requires new drugs against . The 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. potency against recombinant PfPKG and human PKG were used to determine compound selectivity for the parasite enzyme. sporozoites and 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.

PubMed: 38372781
DOI: 10.1021/acs.jmedchem.3c01795

Experimental method

X-RAY DIFFRACTION (2.54 Å)