3FHE: Leukotriene A4 Hydrolase Complexed With Inhibitor N-[3-(4- Benzylphenoxy)propyl]-n-methyl-beta-alanine

Citation:
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.
PDB ID: 3FHEDownload
MMDB ID: 79122
PDB Deposition Date: 2008/12/9
Updated in MMDB: 2011/10 
Experimental Method:
x-ray diffraction
Resolution: 2.16  Å
Source Organism:
Similar Structures:
Biological Unit for 3FHE: monomeric; determined by author and by software (PISA)
Molecular Components in 3FHE
Label Count Molecule
Protein (1 molecule)
1
Leukotriene A-4 Hydrolase
Molecule annotation
Chemicals (7 molecules)
1
1
2
3
3
1
4
1
5
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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