4tn4

Crystal structure of ternary complex of Plasmodium vivax SHMT with glycine and a novel pyrazolopyran 33G: (4S)-6-amino-4-(5-cyano-3'-fluorobiphenyl-3-yl)-4-cyclobutyl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrileCrystal structure of ternary complex of Plasmodium vivax SHMT with glycine and a novel pyrazolopyran 33G: (4S)-6-amino-4-(5-cyano-3'-fluorobiphenyl-3-yl)-4-cyclobutyl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile

Structural highlights 4tn4 is a 3 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: , , , Related: 4pff, 4pfn, 4oyt, 4o6z, 4tmr Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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 A 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. Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT): Cocrystal Structures of Pyrazolopyrans with Potent Blood- and Liver-Stage Activities.,Witschel MC, 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 LM, Charman S, Wittlin S, Yuthavong Y, Chaiyen P, Diederich F J Med Chem. 2015 Mar 18. PMID:25785478 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Serine hydroxymethyltransferase

spinqualitylabelsall models 4tn4, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image