Date published 
April 2012 

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Fragment-Based Drug Discovery: Technologies, Applications, and Pipelines - Overview


Author: Peter Norman, MBA, PhD

Comparison of development candidates derived from fragment-based screens has suggested that such an approach can provide compounds with more drug-like properties than those derived from more conventional screening efforts. The development and application of fragment-based screening methodologies form the focus of this report, which discusses:

  • The rationale for using fragments, considering the advantages from their position in chemical space and as leads for targets that have proved intractable to other methods
  • The various methods that have been described for use in fragment-based screens, highlighting the advantages and disadvantages of the more widely used approaches
  • Case histories that illustrate the success of fragment-based drug design in identifying novel, tractable leads that can be progressed to development candidates
  • Diverse specialist companies that exploit fragment-based screening or that offer services to other organizations that exploit specific aspects of fragment-screening technologies
  • How these developments will impact the future of pharmaceutical R&D with respect to small-molecule therapeutics
  • Findings and analysis from an Insight Pharma Reports survey that was conducted on fragment-based screening 

The screening of low-molecular weight chemicals (fragments) has emerged as a rational, increasingly popular approach for the identification of novel, chemically tractable leads for the development of new therapeutic agents. This Insight Pharma Report, Fragment-Based Drug Discovery: Technologies, Applications, and Pipelines, examines the many issues that must be considered vis-à-vis employment of fragment-based screening approaches. Chemical considerations are examined, including the impact of high-throughput screening (HTS) and its attendant shortcomings, the concept of chemical space, and factors that must be considered when assessing fragment candidates for inclusion in screening libraries. The criteria for selecting possible fragments (Rule of 3), and for assessing contributions to binding (e.g. ligand efficiency), are discussed. The increasing number of different assay protocols that have proven useful in fragment screening are reviewed; these various methods are considered in the context of their specific advantages and limitations.

This Insight Pharma Report presents several case studies illustrating the success of fragment-based drug design in identifying novel, tractable leads that can be progressed to development candidates. Each of these examples highlights the application of different biophysical methods to a specific class of targets.  The increasing popularity of fragment-based screening methods is highlighted by the ever-expanding number of companies that provide fragment-based screening services. We briefly review selected specialist companies, comprising those which have specialized in using fragment-based design to identify their own lead compounds, those which offer specialized fragment-based screening services, and those which provide fragment libraries.

Almost all major pharmaceutical companies have now adopted fragment-based screening programs for at least some of their discovery efforts, while many smaller companies have found the method invaluable for lead identification. This has led to around 30 fragment-derived leads having progressed to clinical development, and one such drug having already gained approval (ZELBORAF [vemurafenib]). Fragment-Based Drug Discovery: Technologies, Applications, and Pipelines concludes with an examination of corporate interest in fragment screening, together with a review of compounds in clinical development that are derived from leads identified in fragment-screening programs. Finally, results from Insight Pharma Reports’ “Fragment-Based Screening” survey are presented and analyzed.

About the Author
Peter Norman, MBA, PhD, is a pharmaceutical consultant and analyst based in Burnham Beeches, near Windsor, England, with specialist knowledge of the respiratory disease and inflammation markets. He has written and presented widely on various aspects of respiratory disease, generics, orphan drugs and developments in therapeutic markets. Dr. Norman has over 20 years’ experience of the pharmaceutical industry in both R&D and competitive intelligence. His publications include many reviews and management reports, sixteen original scientific papers and eleven patents. Dr. Norman holds science degrees from Cambridge University and Brunel University plus an MBA degree from the Open University.