4AL4

Deposited: 2012-03-01 Released: 2012-03-21
Deposition Author(s): Tucker, J.A., Brassington, C., Hassall, G., Ward, R., Tart, J., Davies, G., Hohson, M., Pearson, S.

Experimental Data Snapshot

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

(2012) J Med Chem 55: 3285

PubMed: 22417091 Search on PubMed
DOI: https://doi.org/10.1021/jm201734r
Primary Citation of Related Structures:
4AJ1, 4AJ2, 4AJ4, 4AJE, 4AJH, 4AJI, 4AJJ, 4AJK, 4AJL, 4AJN, 4AJO, 4AJP, 4AL4

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.

Organizational Affiliation

Oncology and Discovery Sciences iMEDs, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. richard.a.ward@astrazeneca.com

Macromolecule Content

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
L-LACTATE DEHYDROGENASE A CHAIN	A, B, C, D	331	Rattus norvegicus	Mutation(s): 0 EC: 1.1.1.27
UniProt
Find proteins for P04642 (Rattus norvegicus) Explore P04642 Go to UniProtKB: P04642
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P04642
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
W7E Query on W7E Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain H [auth B] SDF format, chain I [auth B] SDF format, chain J [auth C] SDF format, chain K [auth C] SDF format, chain L [auth D] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth B] MOL2 format, chain I [auth B] MOL2 format, chain J [auth C] MOL2 format, chain K [auth C] MOL2 format, chain L [auth D]	F [auth A] G [auth A] H [auth B] I [auth B] J [auth C] F [auth A], G [auth A], H [auth B], I [auth B], J [auth C], K [auth C], L [auth D]	2-[[4-[2-[[3-[(2-methyl-1,3-benzothiazol-6-yl)amino]-3-oxidanylidene-propyl]carbamoylamino]ethoxy]phenyl]methyl]propanedioic acid C₂₄ H₂₆ N₄ O₇ S YPEMYPUMNYOIMU-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth B] Focus chain I [auth B] Focus chain J [auth C] Focus chain K [auth C] Focus chain L [auth D] Interactions & Density Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth B] Focus chain I [auth B] Focus chain J [auth C] Focus chain K [auth C] Focus chain L [auth D]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain E [auth A] MOL2 format, chain E [auth A]	E [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Interactions & Density Focus chain E [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
W7E	Binding MOAD: 4AL4	Kd: 130 (nM) from 1 assay(s)
	PDBBind: 4AL4	Kd: 130 (nM) from 1 assay(s)
	BindingDB: 4AL4	Kd: 130 (nM) from 1 assay(s)
	BindingDB: 4AL4	IC50: 4200 (nM) from 1 assay(s)