4qo7

From Proteopedia

Lactate Dehydrogenase A in complex with substituted 3-Hydroxy-2-mercaptocyclohex-2-enone compound 7

PDB ID 4qo7

Drag the structure with the mouse to rotate

Structural highlights

4qo7 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.14Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

LDHA_HUMAN Defects in LDHA are the cause of glycogen storage disease type 11 (GSD11) [MIM:612933. A metabolic disorder that results in exertional myoglobinuria, pain, cramps and easy fatigue.^[1]

Function

LDHA_HUMAN

Publication Abstract from PubMed

A novel class of 3-hydroxy-2-mercaptocyclohex-2-enone-containing inhibitors of human lactate dehydrogenase (LDH) was identified through a high-throughput screening approach. Biochemical and surface plasmon resonance experiments performed with a screening hit (LDHA IC50=1.7muM) indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of this screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50=0.18muM). Two crystal structures of optimized compounds bound to human LDHA were obtained and explained many of the observed structure-activity relationships. In addition, an optimized inhibitor exhibited good pharmacokinetic properties after oral administration to rats (F=45%).

Identification of substituted 3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase.,Dragovich PS, Fauber BP, Boggs J, Chen J, Corson LB, Ding CZ, Eigenbrot C, Ge H, Giannetti AM, Hunsaker T, Labadie S, Li C, Liu Y, Liu Y, Ma S, Malek S, Peterson D, Pitts KE, Purkey HE, Robarge K, Salphati L, Sideris S, Ultsch M, VanderPorten E, Wang J, Wei B, Xu Q, Yen I, Yue Q, Zhang H, Zhang X, Zhou A Bioorg Med Chem Lett. 2014 Aug 15;24(16):3764-71. doi:, 10.1016/j.bmcl.2014.06.076. Epub 2014 Jul 1. PMID:25037916^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Maekawa M, Sudo K, Kanno T, Li SS. Molecular characterization of genetic mutation in human lactate dehydrogenase-A (M) deficiency. Biochem Biophys Res Commun. 1990 Apr 30;168(2):677-82. PMID:2334430
↑ Dragovich PS, Fauber BP, Boggs J, Chen J, Corson LB, Ding CZ, Eigenbrot C, Ge H, Giannetti AM, Hunsaker T, Labadie S, Li C, Liu Y, Liu Y, Ma S, Malek S, Peterson D, Pitts KE, Purkey HE, Robarge K, Salphati L, Sideris S, Ultsch M, VanderPorten E, Wang J, Wei B, Xu Q, Yen I, Yue Q, Zhang H, Zhang X, Zhou A. Identification of substituted 3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase. Bioorg Med Chem Lett. 2014 Aug 15;24(16):3764-71. doi:, 10.1016/j.bmcl.2014.06.076. Epub 2014 Jul 1. PMID:25037916 doi:http://dx.doi.org/10.1016/j.bmcl.2014.06.076