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Klein J.,Evolva SA | Heal J.R.,Prosarix Ltd | Hamilton W.D.O.,Prosarix Ltd | Boussemghoune T.,Evolva SA | And 5 more authors.
ACS Synthetic Biology | Year: 2014

Synthetic biology has been heralded as a new bioengineering platform for the production of bulk and specialty chemicals, drugs, and fuels. Here, we report for the first time a series of 74 novel compounds produced using a combinatorial genetics approach in bakers yeast. Based on the concept of coevolution with target proteins in an intracellular primary survival assay, the identified, mostly scaffold-sized (200-350 MW) compounds, which displayed excellent biological activity, can be considered as prevalidated hits. Of the molecules found, >75% have not been described previously; 20% of the compounds exhibit novel scaffolds. Their structural and physicochemical properties comply with established rules of drug-and fragment-likeness and exhibit increased structural complexities compared to synthetically produced fragments. In summary, the synthetic biology approach described here represents a completely new, complementary strategy for hit and early lead identification that can be easily integrated into the existing drug discovery process. © 2014 American Chemical Society.


Heal J.,Prosarix Ltd. | Brough S.,Key Organics Ltd.
Sp2 | Year: 2014

KeyFinder libraries have been developed by Key Organics in partnership with Prosarix to provide a cutting-edge service to support early-phase drug discovery.


Bhurruth-Alcor Y.,Imperial College London | Rost T.,University of Bergen | Jorgensen M.R.,Imperial College London | Kontogiorgis C.,Imperial College London | And 7 more authors.
Organic and Biomolecular Chemistry | Year: 2011

Peroxisome proliferator activated receptors (PPARs) have been shown to have critical roles in fatty acid oxidation, triglyceride synthesis, and lipid metabolism - making them an important target in drug discovery. Here we describe the in silico design, synthesis and in vitro characterisation of a novel series of 2,5-disubstituted indoles as PPARα/γ dual agonists. PPAR activation assays are performed with known agonists diazabenzene (WY14.643), aminopyridine (BRL49653) and bisaryl (L165.041), as positive controls. All the indole compounds synthesized are found to be active PPARα and PPARγ agonists, with particular efficacy from those with 2-naphthylmethyl substitution. This is a useful demonstration of a new de novo design methodology implemented by the protobuild program and its ability to rapidly produce novel modulators for a well characterized drug target. © 2011 The Royal Society of Chemistry.

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