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-carbonitrile

Citation:
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 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.
PDB ID: 4TN4Download
MMDB ID: 128077
PDB Deposition Date: 2014/6/3
Updated in MMDB: 2017/12
Experimental Method:
x-ray diffraction
Resolution: 2.2  Å
Source Organism:
Similar Structures:
Biological Unit for 4TN4: dimeric; determined by author and by software (PISA)
Molecular Components in 4TN4
Label Count Molecule
Proteins (2 molecules)
2
Serine Hydroxymethyltransferase
Molecule annotation
Chemicals (7 molecules)
1
2
2
2
3
2
4
1
* Click molecule labels to explore molecular sequence information.

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