Fragments of Life – Enhancing Efficiency in Drug Discovery
News Jul 24, 2009
deCODE chemistry & biostructures has announced publication of an article entitled “Discovery of Leukotriene A4 Hydrolase Inhibitors Using Metabolomics Biased Fragment Crystallography” in the Journal of Medicinal Chemistry (Journal of Medicinal Chemistry, Electronic Publication July 20, 2009).
The article describes a novel fragment library termed Fragments of Life™ (FOL) for structure-based drug discovery. The FOL library includes natural small molecules of life, derivatives thereof, and biaryl protein architecture mimetics.
The choice of fragments facilitates the interrogation of protein active sites, allosteric binding sites, and protein-protein interaction surfaces for fragment binding. deCODE’s Fragments of Life (FOL) library was screened against Leukotriene A4 Hydrolase (LTA4H) by X-ray crystallography, allowing the discovery of a diverse array of fragments including derivatives of resveratrol, nicotinamide, and indole as efficient ligands for binding and inhibiting LTA4H. These fragments embody key chemical features and binding modes of several reported LTA4H inhibitors. Three of the fragments were elaborated into potent inhibitors of LTA4H representing multiple novel chemotypes for modulating leukotriene biosynthesis.
According to Dr. Doug Davies, Senior Director of Structural Biology at deCODE and first author of the ACS publication, “Fragments of Life is more than just a fragment library, it is a sound approach to identifying key starting point ligand architectures that have high ligand efficiency for binding to the target of interest. Library components not only have high binding efficiency but also exhibit other drug-like properties such as mM solubility characteristics and complimentary surface and shape properties to proteins”.
Also, deCODE biostructures recently announced the signing of the fourth Fragments of Life(FOL) screening campaign for lead discovery. deCODE’s FOL clients include InterMune, Achaogen, UCB and Mitsubishi Tanabe Pharma Corporation.
New Chemical Synthesis Process: Synergy of Two Catalysts in One FlaskNews
Researchers report the one-step synthesis of a ketone from an aldehyde by the combination of thiazolium N-heterocyclic carbene and palladium/bisphosphine catalysts in one flask. The two catalysts function in a synergistic manner. This study is expected to lead to new synthesis processes of precursor compounds for medications.READ MORE