Fragment-based drug discovery

Heptares Therapeutics Ltd, a drug discovery company creating new medicines targeting G-protein-coupled receptors (GPCRs), has published findings that demonstrate important advances in the application of fragment screening to GPCRs.

In a recent publication in the influential Methods in Enzymology [ref.1], Congreve et al. describe the successful application of fragment screening to multiple GPCR targets that were stabilised, for the first time, using the Heptares StaR technology.

Fragment-based drug discovery (FBDD) approaches have emerged as a powerful tool for discovering and optimizing new and improved compounds against selected disease targets. However, fragment screening requires structural information about the disease target as a starting point. While such structural information has been readily available for soluble proteins, such as kinases and proteases, GPCRs are highly unstable when extracted from the cell membrane, preventing scientists from obtaining structural information that would enable fragment screening.

Heptares has solved the problem of GPCR stabilisation with its proprietary StaR technology, allowing resolution of GPCR structures with both Biophysical Mapping and X-ray crystallography methods. By deploying this structural information in fragment screening, the authors found that StaRs identified multiple novel chemotypes that bind at functionally relevant sites on GPCRs.

The importance of having structural information on a target in relation to drug discovery is highlighted in a separate recent publication in Nature Reviews Drug Discovery. Here, Heptares and others reviewed the stage of drug discovery programmes on 20 targets, ten enzymes which had structural information available and ten GPCRs with very limited available structural information. The analysis found that 2-3 times more drug discovery programmes were active on targets with structural information available, and significantly fewer programmes failed or were discontinued [ref. 2].

“The exciting findings by Heptares scientists and our collaborators signify an important advance in the application of powerful fragment- and structure-based drug discovery approaches to GPCRs,” said Malcolm Weir, CEO of Heptares Therapeutics. “These important drug targets can now be investigated using the same techniques that have proved highly successful for other major target families and we believe will deliver important breakthroughs that lead to new candidate medicines over the coming years.”


1. Congreve. M. et al. (2011) Fragment Screening of Stabilized G-Protein Coupled Receptors Using Biophysical Methods. Methods Enzymol., Vol. 493, Chapter 5: Academic Press. Lawrence C. Kuo ed.

2. Borshall, N. and Congreve, M. (2011) Valuation Benefits of Structure-enabled Drug Discovery. Nat. Rev. Drug. Disc. 10 (166) (News and Analysis, March 2011)

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