3FHE

Leukotriene A4 Hydrolase complexed with inhibitor N-[3-(4-benzylphenoxy)propyl]-N-methyl-beta-alanine.

3FHE の概要

• エントリーDOI: 10.2210/pdb3fhe/pdb
• 関連するPDBエントリー: 3FH5 3FH7 3FH8
• 分子名称: Leukotriene A-4 hydrolase, ZINC ION, YTTERBIUM (III) ION, ... (7 entities in total)
• 機能のキーワード: lta4h, leukotriene a4, leukotriene b4 biosynthesis, peptidase, hydrolase-hydrolase inhibitor complex, structure based drug design, leukotriene biosynthesis, metal-binding, metalloprotease, multifunctional enzyme, protease, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 70404.04

構造登録者

Mamat, B.,Davies, D.R. (登録日: 2008-12-09, 公開日: 2010-01-05, 最終更新日: 2023-11-29)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.16 Å)