PDB 3FTZ deposited: 2009-01-13 modified: 2011-07-13
Title Leukotriene A4 hydrolase in complex with fragment 2-(pyridin-3-ylmethoxy)aniline
Authors Andresson, T., Davies, D.R., Enache, L., Gurney, M.E., Halldorsdottir, G., Keyvan, M., Kiselyov, A.S., Krohn, M., Mamat, B., Mishra, R.K., Onua, E., Sandanayaka, V., Sigthorsdottir, H., Sigthorsson, G., Singh, J., Stewart, L.J., Sullins, D., Thorlaksdottir, A., Thorsteinnsdottir, M., Winger, J., Zembower, D.E., Zhang, J., Zhou, L.M.
Structure factors resolution 2.0 rfactor 0.183 rfree 0.223
DPI 0.42 theoretical min: 0.18
Related PDB Entries 3FH5 3FH7 3FH8 3FHE 3FUL

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.

J.Med.Chem. 2010 Jan; 53(2):573-585 doi:10.1021/jm900838g

Cross References
Database source Identifier Description
ChEMBL Document CHEMBL1156785
PubMed 19950900 JMCMAR
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
3FTZ/0 3FTZ 0 monomer 0 1 8 4539