The methods of fragment-based lead discovery (FBLD) have matured considerably and are an accepted part of the armory of techniques used to identify initial hit compounds for initiating either a chemical biology or drug discovery project. This chapter reviews the evolution of the methods and summarizes the essential features of a fragment-based discovery platform, illustrated with some recent success stories. It presents some extended discussion of some of the practical aspects of fragments based on the author's experiences and the literature. A fragment-based discovery campaign has three main components - a library of fragments, a method for identifying which fragments bind to the target (screening), and a strategy for evolving the fragments to hits that register in conventional assays. One key point is that as many orthogonal techniques should be applied, and their output interpreted skeptically, to identify an optimal set of validated fragment hits.
|Title of host publication
|Structural Biology in Drug Discovery
|Subtitle of host publication
|Methods, Techniques, and Practices
|Number of pages
|Published - 1 Jan 2020
Bibliographical notePublisher Copyright:
© 2020 John Wiley & Sons, Inc. All rights reserved.
- fragment evolution
- fragment hits
- fragment libraries
- fragment screening
- fragment-based ligand discovery