5w8i | pdb_00005w8i

Crystal Structure of Lactate Dehydrogenase A in complex with inhibitor compound 23 and Zinc

spinqualitylabelsall models 5w8i, resolution 1.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5w8i is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.95Å Ligands: 9YD, CIT, DMS, GOL, MLA, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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. Function LDHA_HUMAN Publication Abstract from PubMed We report the discovery and medicinal chemistry optimization of a novel series of pyrazole-based inhibitors of human lactate dehydrogenase (LDH). Utilization of a quantitative high-throughput screening paradigm facilitated hit identification, while structure-based design and multiparameter optimization enabled the development of compounds with potent enzymatic and cell-based inhibition of LDH enzymatic activity. Lead compounds such as 63 exhibit low nM inhibition of both LDHA and LDHB, submicromolar inhibition of lactate production, and inhibition of glycolysis in MiaPaCa2 pancreatic cancer and A673 sarcoma cells. Moreover, robust target engagement of LDHA by lead compounds was demonstrated using the cellular thermal shift assay (CETSA), and drug-target residence time was determined via SPR. Analysis of these data suggests that drug-target residence time (off-rate) may be an important attribute to consider for obtaining potent cell-based inhibition of this cancer metabolism target. Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH).,Rai G, Brimacombe KR, Mott BT, Urban DJ, Hu X, Yang SM, Lee TD, Cheff DM, Kouznetsova J, Benavides GA, Pohida K, Kuenstner EJ, Luci DK, Lukacs CM, Davies DR, Dranow DM, Zhu H, Sulikowski G, Moore WJ, Stott GM, Flint AJ, Hall MD, Darley-Usmar VM, Neckers LM, Dang CV, Waterson AG, Simeonov A, Jadhav A, Maloney DJ J Med Chem. 2017 Nov 22;60(22):9184-9204. doi: 10.1021/acs.jmedchem.7b00941. Epub, 2017 Nov 9. PMID:29120638 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Lactate dehydrogenase 3D structures

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