| Structural highlights
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]
Publication Abstract from PubMed
Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enone using structure-based design strategies resulted in inhibitors with considerable improvement in biochemical potency against human lactate dehydrogenase A (LDHA). These potent inhibitors were typically selective for LDHA over LDHB isoform (4-10 fold) and other structurally related malate dehydrogenases, MDH1 and MDH2 (>500 fold). An X-ray crystal structure of enzymatically most potent molecule bound to LDHA revealed two additional interactions associated with enhanced biochemical potency.
Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase.,Labadie S, Dragovich PS, Chen J, Fauber BP, Boggs J, Corson LB, Ding CZ, Eigenbrot C, Ge H, Ho Q, Lai KW, Ma S, Malek S, Peterson D, Purkey HE, Robarge K, Salphati L, Sideris S, Ultsch M, VanderPorten E, Wei B, Xu Q, Yen I, Yue Q, Zhang H, Zhang X, Zhou A Bioorg Med Chem Lett. 2014 Nov 10;25(1):75-82. doi: 10.1016/j.bmcl.2014.11.008. PMID:25466195[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
- ↑ Labadie S, Dragovich PS, Chen J, Fauber BP, Boggs J, Corson LB, Ding CZ, Eigenbrot C, Ge H, Ho Q, Lai KW, Ma S, Malek S, Peterson D, Purkey HE, Robarge K, Salphati L, Sideris S, Ultsch M, VanderPorten E, Wei B, Xu Q, Yen I, Yue Q, Zhang H, Zhang X, Zhou A. Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase. Bioorg Med Chem Lett. 2014 Nov 10;25(1):75-82. doi: 10.1016/j.bmcl.2014.11.008. PMID:25466195 doi:http://dx.doi.org/10.1016/j.bmcl.2014.11.008
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