The View From Here

Mark Whittaker

Fragment-Based Drug Discovery

Fragment-based drug discovery is a new rational approach to drug hunting that is being embraced by both pharmaceutical and biotech companies. Traditionally, small molecule leads have been identified using techniques such as high throughput screening whereby a compound is identified that binds or interacts with the protein target of interest at a relatively low concentration.  This is a well accepted technology for identifying starting points for future drugs.  The subsequent optimisation of the initial hit compounds can be a laborious task and somewhat hit and miss if no structural information is available.  One limitation of this technique is that the hit compounds tend to be of a similar molecular weight and size to the final drug and have low ligand efficiency.  Thus, subsequent modifications to the chemical structures require deletion and addition of functionality.  A fragment-based approach offers a solution to this for proteins that are amenable to such an approach.  It is a technique that allows for the identification of lower molecular weight compounds (called fragments) at much higher concentrations with high ligand efficiencies.  One can imagine the fragments as the simplest chemical start points for the resultant drug.  Given the petite size of these starting points, chemical modification is usually limited to the addition of a small number of key functional groups to improve the potency and properties of the compounds.  So in general, when compared to the more traditional high throughput screening approach, a much lower number of compounds need to be synthesised to obtain the subsequent development candidate, thus improving the efficiency and effectiveness of the drug discovery process.

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Mark Whittaker

Mark Whittaker is Senior Vice President Drug Discovery, where he manages a large drug discovery collaboration and the groups of computational chemistry and structural biology. Prior to joining Evotec in 2001, Mark spent 13 years at British Biotech Pharmaceuticals, where he led a number of medicinal chemistry programmes and was latterly Director of Chemistry. At British Biotech, Mark contributed to the discovery and development of six compounds that have progressed into human clinical trials. Prior to his career at British Biotech, Mark carried out postdoctoral research at the University of Oxford and at York University, Toronto and obtained a DPhil in Chemistry from the University of York.