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Fragment approaches in structure-based drug discovery.

Hubbard RE - J Synchrotron Radiat (2008)

Bottom Line: The main advantage is that a larger potential chemical diversity can be sampled with fewer compounds, which is particularly important for new target classes.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Vernalis (R&D) Ltd and University of York, UK. rod@ysbl.york.ac.uk

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.

Show MeSH
Constructing a fragment library: an example of the pipeline of cheminformatics calculations used to identify suitable compounds to include in a fragment library.
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fig1: Constructing a fragment library: an example of the pipeline of cheminformatics calculations used to identify suitable compounds to include in a fragment library.

Mentions: The essential steps are summarized in Fig. 1 ▶ and consist of selecting a library of suitable fragments, identifying which fragments bind to the target binding site using NMR or surface plasmon resonance methods, determination of the structure of the fragments binding to the protein by X-ray crystallography, and then using the structural information to guide the evolution of improved hit or lead compounds.


Fragment approaches in structure-based drug discovery.

Hubbard RE - J Synchrotron Radiat (2008)

Constructing a fragment library: an example of the pipeline of cheminformatics calculations used to identify suitable compounds to include in a fragment library.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2394783&req=5

fig1: Constructing a fragment library: an example of the pipeline of cheminformatics calculations used to identify suitable compounds to include in a fragment library.
Mentions: The essential steps are summarized in Fig. 1 ▶ and consist of selecting a library of suitable fragments, identifying which fragments bind to the target binding site using NMR or surface plasmon resonance methods, determination of the structure of the fragments binding to the protein by X-ray crystallography, and then using the structural information to guide the evolution of improved hit or lead compounds.

Bottom Line: The main advantage is that a larger potential chemical diversity can be sampled with fewer compounds, which is particularly important for new target classes.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Vernalis (R&D) Ltd and University of York, UK. rod@ysbl.york.ac.uk

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.

Show MeSH