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

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.