3FUL

Leukotriene A4 hydrolase in complex with pyridin-4-yl[4-(2-pyrrolidin-1-ylethoxy)phenyl]methanone

Summary for 3FUL

• Entry DOI: 10.2210/pdb3ful/pdb
• Related: 3FH7 3FTS 3FTU 3FTV 3FTW 3FTX 3FTY 3FTZ 3FU0 3FU3 3FU5 3FU6 3FUD 3FUE 3FUF 3FUH 3FUI 3FUJ 3FUK 3FUM 3FUN
• Descriptor: Leukotriene A-4 hydrolase, ZINC ION, YTTERBIUM (III) ION, ... (6 entities in total)
• Functional Keywords: leukotriene a4 hydrolase, lta4h, fragment crystallography, fragments of life, fol, hydrolase-hydrolase inhibitor complex, leukotriene biosynthesis, metal-binding, metalloprotease, multifunctional enzyme, protease, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P09960
• Total number of polymer chains: 1
• Total formula weight: 70036.95

Authors

Davies, D.R. (deposition date: 2009-01-14, release date: 2010-01-05, Last modification date: 2023-09-06)

Primary citation

Sandanayaka, V.,Mamat, B.,Mishra, R.K.,Winger, J.,Krohn, M.,Zhou, L.M.,Keyvan, M.,Enache, L.,Sullins, D.,Onua, E.,Zhang, J.,Halldorsdottir, G.,Sigthorsdottir, H.,Thorlaksdottir, A.,Sigthorsson, G.,Thorsteinnsdottir, M.,Davies, D.R.,Stewart, L.J.,Zembower, D.E.,Andresson, T.,Kiselyov, A.S.,Singh, J.,Gurney, M.E.
Discovery of 4-[(2S)-2-{[4-(4-chlorophenoxy)phenoxy]methyl}-1-pyrrolidinyl]butanoic acid (DG-051) as a novel leukotriene A4 hydrolase inhibitor of leukotriene B4 biosynthesis.
J.Med.Chem., 53:573-585, 2010

PubMed Abstract: Both in-house human genetic and literature data have converged on the identification of leukotriene 4 hydrolase (LTA(4)H) as a key target for the treatment of cardiovascular disease. We combined fragment-based crystallography screening with an iterative medicinal chemistry effort to optimize inhibitors of LTA(4)H. Ligand efficiency was followed throughout our structure-activity studies. As applied within the context of LTA(4)H inhibitor design, the chemistry team was able to design a potent compound 20 (DG-051) (K(d) = 26 nM) with high aqueous solubility (>30 mg/mL) and high oral bioavailability (>80% across species) that is currently undergoing clinical evaluation for the treatment of myocardial infarction and stroke. The structural biology-chemistry interaction described in this paper provides a sound alternative to conventional screening techniques. This is the first example of a gene-to-clinic paradigm enabled by a fragment-based drug discovery effort.

PubMed: 19950900
DOI: 10.1021/jm900838g

Experimental method

X-RAY DIFFRACTION (2.39 Å)