Over the past ten years, there has been increasing interest in fragment based methods for drug discovery. The excitement (and investment) in the methods has grown over the past few years as a number of compounds have entered clinical trials where fragment derived information has made important contributions. The central premise is that a small library of compounds can sample a potentially huge chemical diversity. The structure of hit fragments binding to an active site can then guide medicinal chemists to rapidly expand and optimise these hits into leads and then onto candidates. This provides an attractive alternative to High Throughput Screening for identifying tractable starting points for generation of novel lead compounds, particularly for new classes of target.
Fragments are just small, weak hits. The developments of the past few years have mainly been driven by small, technology focussed companies and have provided methods and experience in the design of fragment libraries and a range of biophysical methods to identify and characterise fragment binding to a target active site. The result is that for most targets, a large number of diverse fragments can be identified binding to an active site, sampling many different interactions. The main issues are now deciding how to analyse and exploit this richness of protein-ligand interaction data.
In many ways, this re-emphasises the challenges that have been faced by structure-based design for the past two decades - scoring functions and designing compounds that are chemically tractable.
This conference will include some review lectures, highlighting the latest examples and methods of fragment based discovery. But the main emphasis will be on how to exploit structural information in fragment-based ligand discovery.
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