4TMR

Crystal structure of ternary complex of Plasmodium vivax SHMT with glycine and a novel pyrazolopyran 99S: methyl 5-{3-[(4S)-6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl}thiophene-2-carboxylate .

Summary for 4TMR

• Entry DOI: 10.2210/pdb4tmr/pdb
• Related: 4O6Z 4OYT 4PFF 4PFN 4TN4
• Descriptor: Serine hydroxymethyltransferase, putative, N-GLYCINE-[3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YL-METHANE], methyl 5-{3-[(4S)-6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl}thiophene-2-carboxylate, ... (5 entities in total)
• Functional Keywords: alpha and beta protein, transferase, methyltransferase activity, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Plasmodium vivax
• Total number of polymer chains: 3
• Total formula weight: 150115.57

Authors

Chitnumsub, P.,Jaruwat, A.,Leartsakulpanich, U.,Witschel, M.C. (deposition date: 2014-06-02, release date: 2015-03-25, Last modification date: 2023-09-27)

Primary citation

Witschel, M.C.,Rottmann, M.,Schwab, A.,Leartsakulpanich, U.,Chitnumsub, P.,Seet, M.,Tonazzi, S.,Schwertz, G.,Stelzer, F.,Mietzner, T.,McNamara, C.,Thater, F.,Freymond, C.,Jaruwat, A.,Pinthong, C.,Riangrungroj, P.,Oufir, M.,Hamburger, M.,Maser, P.,Sanz-Alonso, L.M.,Charman, S.,Wittlin, S.,Yuthavong, Y.,Chaiyen, P.,Diederich, F.
Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT): Cocrystal Structures of Pyrazolopyrans with Potent Blood- and Liver-Stage Activities.
J.Med.Chem., 58:3117-3130, 2015

PubMed Abstract: Several of the enzymes related to the folate cycle are well-known for their role as clinically validated antimalarial targets. Nevertheless for serine hydroxymethyltransferase (SHMT), one of the key enzymes of this cycle, efficient inhibitors have not been described so far. On the basis of plant SHMT inhibitors from an herbicide optimization program, highly potent inhibitors of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) SHMT with a pyrazolopyran core structure were identified. Cocrystal structures of potent inhibitors with PvSHMT were solved at 2.6 Å resolution. These ligands showed activity (IC50/EC50 values) in the nanomolar range against purified PfSHMT, blood-stage Pf, and liver-stage P. berghei (Pb) cells and a high selectivity when assayed against mammalian cell lines. Pharmacokinetic limitations are the most plausible explanation for lack of significant activity of the inhibitors in the in vivo Pb mouse malaria model.

PubMed: 25785478
DOI: 10.1021/jm501987h

Experimental method

X-RAY DIFFRACTION (2.7 Å)