Fragment approaches in structure-based drug discovery

Roderick E. Hubbard

doi:10.1107/S090904950705666X

Fragment approaches in structure-based drug discovery

Roderick E. Hubbard

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

There has been considerable interest recently in what is known as 'fragment-based lead discovery'. The novel feature of the approach is to begin with small low-affinity compounds. The main advantage is that a larger potential chemical diversity can be sampled with fewer compounds, which is particularly important for new target classes. The approach relies on careful design of the fragment library, a method that can detect binding of the fragment to the protein target, determination of the structure of the fragment bound to the target, and the conventional use of structural information to guide compound optimization. In this article the methods are reviewed, and experiences in fragment-based discovery of lead series of compounds against kinases such as PDK1 and ATPases such as Hsp90 are discussed. The examples illustrate some of the key benefits and issues of the approach and also provide anecdotal examples of the patterns seen in selectivity and the binding mode of fragments across different protein targets.

Original language	English
Pages (from-to)	227-230
Number of pages	4
Journal	Journal of Synchrotron Radiation
Volume	15
Issue number	3
DOIs	https://doi.org/10.1107/S090904950705666X
Publication status	Published - 18 May 2008

Keywords

IN-VITRO
PROTEIN
INHIBITORS
DESIGN
NMR
IDENTIFICATION
LIGANDS
HSP90
VIVO
PDK1

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Fragment approaches in structure-based drug discovery

Abstract

Keywords

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