4QO8

Lactate Dehydrogenase A in complex with substituted 3-Hydroxy-2-mercaptocyclohex-2-enone compound 104

Summary for 4QO8

• Entry DOI: 10.2210/pdb4qo8/pdb
• Related: 4QO7
• Descriptor: L-lactate dehydrogenase A chain, 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (7 entities in total)
• Functional Keywords: oxidoreductase, nicotinamide adenine dinucleotide, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P00338
• Total number of polymer chains: 4
• Total formula weight: 151464.06

Authors

Eigenbrot, C.,Ultsch, M. (deposition date: 2014-06-19, release date: 2014-07-16, Last modification date: 2023-11-15)

Primary citation

Dragovich, P.S.,Fauber, B.P.,Boggs, J.,Chen, J.,Corson, L.B.,Ding, C.Z.,Eigenbrot, C.,Ge, H.,Giannetti, A.M.,Hunsaker, T.,Labadie, S.,Li, C.,Liu, Y.,Liu, Y.,Ma, S.,Malek, S.,Peterson, D.,Pitts, K.E.,Purkey, H.E.,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., 24:3764-3771, 2014

PubMed Abstract: 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=1.7 μM) 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=0.18 μM). 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%).

PubMed: 25037916
DOI: 10.1016/j.bmcl.2014.06.076

Experimental method

X-RAY DIFFRACTION (2.001 Å)