3FTZ: Leukotriene A4 Hydrolase In Complex With Fragment 2-(pyridin-3- Ylmethoxy)aniline

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: 3FTZDownload
MMDB ID: 79124
PDB Deposition Date: 2009/1/13
Updated in MMDB: 2010/08
Experimental Method:
x-ray diffraction
Resolution: 2  Å
Source Organism:
Similar Structures:
Biological Unit for 3FTZ: monomeric; determined by author and by software (PISA)
Molecular Components in 3FTZ
Label Count Molecule
Protein (1 molecule)
1
Leukotriene A-4 Hydrolase(Gene symbol: LTA4H)
Molecule annotation
Chemicals (8 molecules)
1
1
2
1
3
1
4
3
5
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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