1T2E: Plasmodium Falciparum Lactate Dehydrogenase S245a, A327p Mutant Complexed With Nadh And Oxamate

Citation:
Abstract
Plasmodium falciparum, the causative agent of malaria, relies extensively on glycolysis coupled with homolactic fermentation during its blood-borne stages for energy production. Selective inhibitors of the parasite lactate dehydrogenase (LDH), central to NAD(+) regeneration, therefore potentially provide a route to new antimalarial drugs directed against a novel molecular target. A series of heterocyclic, azole-based compounds are described that preferentially inhibit P. falciparum LDH at sub-micromolar concentrations, typically at concentrations about 100-fold lower than required for human lactate dehydrogenase inhibition. Crystal structures show these competitive inhibitors form a network of interactions with amino acids within the active site of the enzyme, stacking alongside the nicotinamide ring of the NAD(+) cofactor. These compounds display modest activity against parasitized erythrocytes, including parasite strains with known resistance to existing anti-malarials and against Plasmodium berghei in BALB/c mice. Initial toxicity data suggest the azole derivatives have generally low cytotoxicity, and preliminary pharmoco-kinetic data show favorable bioavailability and circulation times. These encouraging results suggest that further enhancement of these structures may yield candidates suitable for consideration as new therapeutics for the treatment of malaria. In combination these studies also provide strong support for the validity of targeting the Plasmodium glycolytic pathway and, in particular, LDH in the search for novel anti-malarials.
PDB ID: 1T2EDownload
MMDB ID: 27916
PDB Deposition Date: 2004/4/21
Updated in MMDB: 2007/10
Experimental Method:
x-ray diffraction
Resolution: 1.85  Å
Source Organism:
Similar Structures:
Biological Unit for 1T2E: tetrameric; determined by author and by software (PISA,PQS)
Molecular Components in 1T2E
Label Count Molecule
Proteins (4 molecules)
4
L-lactate Dehydrogenase
Molecule annotation
Chemicals (12 molecules)
1
4
2
4
3
4
* Click molecule labels to explore molecular sequence information.

Citing MMDB
.