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European Biopharmaceutical Review

Hunting Down the Drugs

Markus Schade, Thomas Hesterkamp, John Barker and Mark Whittaker at Evotec turn the spotlight on screening strategies for efficient lead generation by fragment-based drug discovery

Fragment-based drug discovery (FBDD) is a new, rational approach to drug hunting that is being embraced by both pharmaceutical and biotech companies (1). FBDD involves the screening of low molecular weight molecules and the subsequent ability to pursue structure-guided medicinal chemistry optimisation. Fragment screening can be undertaken by a variety of methods. Two complementary techniques are the highly sensitive NMR approach and the use of high concentration biochemical assays. Medicinal chemistry optimisation to improve the potency of the initially identified weakly active fragments is then facilitated by the use of NMR methods and/or X-ray crystallography to determine key interactions and the binding mode of fragment molecules to the target protein.

Drug discovery requires a constant supply of novel and efficient starting points for medicinal chemistry modification. Many techniques have been employed over the years to identify chemical matter, for example high-throughput screening (HTS), high-content screening (HCS) and virtual screening. FBDD is conducted with the pharmaceutical and biotechnology industries by the combination of a number of techniques, but all follow the same generic path of screening, in order to identify weakly active fragment molecules, and subsequent determination of how each active fragment binds to the target protein followed by structuredriven medicinal chemistry optimisation of the fragments into leads. The challenge to identify weakly active fragments has led to a wide variety of fragment screening methods being developed, including high-throughput crystallography, tethering and surfaceplasmon resonance.

This review focuses on two other key methods which exhibit high complementarity, fragment screening by nuclear magnetic resonance (NMR) (2,3) and by biochemical assays (4), as well as how these form the basis of effective lead generation when allied to structural information either obtained by NMR and/or by X-ray crystallography.

FRAGMENT-BASED DRUG DISCOVERY

FBDD is limited to soluble protein targets for which structural information can be obtained. This is because accurate information on how weakly binding fragment molecules interact with a target protein is required to fast-track the medicinal chemistry optimisation through the application of structure-based design methods.

FBDD has advantages over traditional approaches in terms of:

  • Speed – by starting from fragments with high ligand efficiency and using an iterative structure-based approach from the outset, rapid, incremental step increases in ligand potency can be achieved. This is in contrast to the need to reduce HTS hits in size and complexity in order to identify the relevant pharmacophore. The ligand efficiency concept (5) can be used to guide the medicinal chemistry optimisation of fragment compounds (6).
  • Lower attrition – utilising small, highly soluble starting points desired druglike physicochemical/ADMET properties can be designed in at an early stage.
  • Novel chemical IP – excellent coverage of chemical diversity space ensures novel starting points.

A key step in the process is identifying the weakly active fragment starting points in the first place. A variety of screening methods for fragments have been described and each has its merits, but the combination of NMR methods with robust, high concentration biochemical assays provides an approach to fragment screening with broad applicability across different target classes.


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Markus Schade heads Evotec’s NMR Drug Discovery group, which he co-founded as one business line of Combinature Biopharm AG. Markus studied Biochemistry at the University of Hannover, Germany, and joined the group of Professor Alexander Rich, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, for his PhD. He graduated from the Free University of Berlin, Germany.

Thomas Hesterkamp leads the Biochemical Assays group within Evotec’s Biology Services Division based in Hamburg. In that role he oversees processes from reagent production, assay development to HTS and lead generation biology. Before joining Evotec in 2000 he spent three years with the Swiss pharmaceutical company Arpida as a Research Scientist. Thomas graduated in Human Biology at the University of Marburg, Germany, where he also obtained his PhD in 1997.

John Barker is the Group Leader of the Structural Biology team at Evotec, based at Evotec’s Discovery Chemistry site in Oxfordshire. He joined Evotec three years ago to establish the structural biology group and assist in the development of a fragment screening platform. Prior to joining Evotec, John was Director of Structural Biology at PanTherix. John gained his PhD in Chemistry from the University of Bristol.

Mark Whittaker is Senior Vice President Drug Discovery at Evotec, 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. 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.

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Markus Schade
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Thomas Hesterkamp
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John Barker
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Mark Whittaker
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