4AJP

Human LDHA in complex with 2-((4-(4-((3-((2-methyl-1,3-benzothiazol- 6yl)amino)-3-oxo-propyl)amino)-4-oxo-butyl)phenyl)methyl)propanedioic acid

Summary for 4AJP

• Entry DOI: 10.2210/pdb4ajp/pdb
• Related: 1I10 4AJ1 4AJ2 4AJ4 4AJE 4AJH 4AJI 4AJJ 4AJK 4AJL 4AJN 4AJO
• Descriptor: L-LACTATE DEHYDROGENASE A CHAIN, {4-[4-({3-[(2-METHYL-1,3-BENZOTHIAZOL-6-YL)AMINO]-3-OXOPROPYL}AMINO)-4-OXOBUTYL]BENZYL}PROPANEDIOIC ACID, SULFATE ION, ... (5 entities in total)
• Functional Keywords: oxidoreductase-inhibitor complex, fragment based lead generated inhibitors, oxidoreductase/inhibitor
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: P00338
• Total number of polymer chains: 4
• Total formula weight: 153052.60

Authors

Tucker, J.A.,Brassington, C.,Caputo, A.,Ward, R.,Pearson, S.,Watson, M.,Tart, J.,Davies, G. (deposition date: 2012-02-16, release date: 2012-03-21, Last modification date: 2023-12-20)

Primary citation

Ward, R.,Brassington, C.,Breeze, A.L.,Caputo, A.,Critchlow, S.,Davies, G.,Goodwin, L.,Hassall, G.,Greenwood, R.,Holdgate, G.,Mrosek, M.,Norman, R.A.,Pearson, S.,Tart, J.,Tucker, J.A.,Vogtherr, M.,Whittaker, D.,Wingfield, J.,Winter, J.,Hudson, K.
The Design and Synthesis of Novel Lactate Dehydrogenase a Inhibitors by Fragment-Based Lead Generation
J.Med.Chem., 55:3285-, 2012

PubMed Abstract: Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate, utilizing NADH as a cofactor. It has been identified as a potential therapeutic target in the area of cancer metabolism. In this manuscript we report our progress using fragment-based lead generation (FBLG), assisted by X-ray crystallography to develop small molecule LDHA inhibitors. Fragment hits were identified through NMR and SPR screening and optimized into lead compounds with nanomolar binding affinities via fragment linking. Also reported is their modification into cellular active compounds suitable for target validation work.

PubMed: 22417091
DOI: 10.1021/JM201734R

Experimental method

X-RAY DIFFRACTION (2.38 Å)