Heptares scientists report the first use of structure-based drug design to discover GPCR-targeted drug candidate

27-Jan-2012 - United Kingdom

Heptares Therapeutics provided an update on recent scientific publications that highlight its unique ability to generate valuable information on GPCR structures and ligand binding.

In the first of two new papers published in Journal of Medicinal Chemistry, Heptares scientists describe how completely novel antagonists to the adenosine A2A receptor were identified using stabilised receptors (StaRs®) and a virtual screening approach. In silico screening of over half a million compounds resulted in 20 confirmed hits in vitro. These hits lack the undesirable furan and xanthine moieties common to many A2A antagonists. The binding modes of certain of these hits were refined using Heptares’ Biophysical Mapping™, allowing optimal interactions to be identified and potent antagonists designed that proved suitable for further optimisation.

The second J. Med. Chem. Paper describes the structure-based optimisation of one of these series, which led to a preclinical candidate showing, by X-ray crystallography of receptor-ligand complexes, that these compounds bind in a novel mode deep in the orthosteric pocket. The authors describe how atom-efficient design results in leads with excellent pharmacokinetic and pharmacodynamic drug properties, and with best-in-class potential.

Inhibition of the A2A receptor has been proved to be clinically effective in treating symptoms of Parkinson’s disease and may offer benefits in other CNS diseases. A candidate from the novel chemical series discussed is the subject of a partnership with Shire for further development in the area of neurological disorders. This is the first GPCR candidate to be discovered using a fully enabled SBDD process, from virtual screening through multi-parameter optimisation.

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