4I9U

Crystal structure of rabbit LDHA in complex with a fragment inhibitor AP26256

4I9U の概要

• エントリーDOI: 10.2210/pdb4i9u/pdb
• 関連するPDBエントリー: 4I8X 4I9H 4I9N
• 分子名称: L-lactate dehydrogenase A chain, 6-({2-[(5-chloro-2-methoxyphenyl)amino]-2-oxoethyl}sulfanyl)pyridine-3-carboxylic acid (3 entities in total)
• 機能のキーワード: cancer, fragment, inhibitor, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Oryctolagus cuniculus (rabbit)
• 細胞内の位置: Cytoplasm: P13491
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 294673.34

構造登録者

Zhou, T.,Kohlmann, A.,Stephan, Z.G.,Commodore, L.,Greenfield, M.T.,Zhu, X.,Dalgarno, D.C. (登録日: 2012-12-05, 公開日: 2013-01-23, 最終更新日: 2023-09-20)

主引用文献

Kohlmann, A.,Zech, S.G.,Li, F.,Zhou, T.,Squillace, R.M.,Commodore, L.,Greenfield, M.T.,Lu, X.,Miller, D.P.,Huang, W.S.,Qi, J.,Thomas, R.M.,Wang, Y.,Zhang, S.,Dodd, R.,Liu, S.,Xu, R.,Xu, Y.,Miret, J.J.,Rivera, V.,Clackson, T.,Shakespeare, W.C.,Zhu, X.,Dalgarno, D.C.
Fragment growing and linking lead to novel nanomolar lactate dehydrogenase inhibitors.
J.Med.Chem., 56:1023-1040, 2013

PubMed Abstract: Lactate dehydrogenase A (LDH-A) catalyzes the interconversion of lactate and pyruvate in the glycolysis pathway. Cancer cells rely heavily on glycolysis instead of oxidative phosphorylation to generate ATP, a phenomenon known as the Warburg effect. The inhibition of LDH-A by small molecules is therefore of interest for potential cancer treatments. We describe the identification and optimization of LDH-A inhibitors by fragment-based drug discovery. We applied ligand based NMR screening to identify low affinity fragments binding to LDH-A. The dissociation constants (K(d)) and enzyme inhibition (IC(50)) of fragment hits were measured by surface plasmon resonance (SPR) and enzyme assays, respectively. The binding modes of selected fragments were investigated by X-ray crystallography. Fragment growing and linking, followed by chemical optimization, resulted in nanomolar LDH-A inhibitors that demonstrated stoichiometric binding to LDH-A. Selected molecules inhibited lactate production in cells, suggesting target-specific inhibition in cancer cell lines.

PubMed: 23302067
DOI: 10.1021/jm3014844

実験手法

X-RAY DIFFRACTION (2.5 Å)