4i9u

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

spinqualitylabelsall models 4i9u, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4i9u is a 8 chain structure with sequence from Oryctolagus cuniculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 1E7 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function LDHA_RABIT Publication Abstract from PubMed 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. Fragment Growing and Linking Lead to Novel Nanomolar Lactate Dehydrogenase Inhibitors.,Kohlmann A, Zech SG, Li F, Zhou T, Squillace RM, Commodore L, Greenfield MT, Lu X, Miller DP, Huang WS, Qi J, Thomas RM, Wang Y, Zhang S, Dodd R, Liu S, Xu R, Xu Y, Miret JJ, Rivera V, Clackson T, Shakespeare WC, Zhu X, Dalgarno DC J Med Chem. 2013 Jan 9. PMID:23302067 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Lactate dehydrogenase 3D structures

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