4QO8

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

4QO8 の概要

• エントリーDOI: 10.2210/pdb4qo8/pdb
• 関連するPDBエントリー: 4QO7
• 分子名称: L-lactate dehydrogenase A chain, 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (7 entities in total)
• 機能のキーワード: oxidoreductase, nicotinamide adenine dinucleotide, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P00338
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 151464.06

構造登録者

Eigenbrot, C.,Ultsch, M. (登録日: 2014-06-19, 公開日: 2014-07-16, 最終更新日: 2023-11-15)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.001 Å)