6q13 | pdb_00006q13

CRYSTAL STRUCTURE OF LDHA IN COMPLEX WITH COMPOUND NCGC00420737-09 AT 2.00 A RESOLUTION

spinqualitylabelsall models 6q13, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6q13 is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: EDO, NAI, P8V Related: 6q0d Gene: LDHA, PIG19 (HUMAN) Activity: L-lactate dehydrogenase, with EC number 1.1.1.27 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. Publication Abstract from PubMed Lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate, with concomitant oxidation of NADH as the final step in the glycolytic pathway. Glycolysis plays an important role in the metabolic plasticity of cancer cells and has long been recognized as a potential therapeutic target. Thus, potent, selective inhibitors of LDH represent an attractive therapeutic approach. However, to date, pharmacological agents have failed to achieve significant target engagement in vivo, possibly because the protein is present in cells at very high concentrations. We report herein a lead optimization campaign focused on a pyrazole-based series of compounds, using structure-based design concepts, coupled with optimization of cellular potency, in vitro drug-target residence times, and in vivo PK properties, to identify first-in-class inhibitors that demonstrate LDH inhibition in vivo. The lead compounds, named NCATS-SM1440 (43) and NCATS-SM1441 (52) possess desirable attributes for further studying the effect of in vivo LDH inhibition. . Pyrazole-Based Lactate Dehydrogenase (LDH) Inhibitors with Optimized Cell Activity and Pharmacokinetic Properties.,Rai G, Urban DJ, Mott BT, Hu X, Yang SM, Benavides GA, Johnson MS, Squadrito GL, Brimacombe KR, Lee TD, Cheff DM, Zhu H, Henderson MJ, Pohida K, Sulikowski GA, Dranow DM, Kabir M, Shah P, Padilha E, Tao D, Fang Y, Christov PP, Kim K, Jana S, Muttil P, Anderson T, Kunda NK, Hathaway HJ, Kusewitt DF, Oshima N, Cherukuri M, Davies DR, Norenberg JP, Sklar LA, Moore WJ, Dang CV, Stott GM, Neckers LM, Flint AJ, Usmar VD, Simeonov A, Waterson AG, Jadhav A, Hall MD, Maloney DJ J Med Chem. 2020 Sep 9. doi: 10.1021/acs.jmedchem.0c00916. PMID:32902275 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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