Molecular scaffold-based design and comparison of combinatorial libraries focused on the ATP-binding site of protein kinases

Stahura, Florence L.; Xue, Liang; Godden, Jeffrey W.; Bajorath, Jürgen

doi:10.1016/s1093-3263(99)00015-7

Cited by 30 publications

(15 citation statements)

References 27 publications

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“…The Scaffold Tree analysis identified 188 unique rings and 15 types of linkers which constitute 721 different scaffolds in VER_ref. To assess the quality and the coverage of chemical space, benchmark scaffolds were compiled from four studies which described the Vertex SHAPES library [38], Novartis bioactive rings [39], Lilly's analysis of Phase II or later compounds [40] and 72 kinase-targeted scaffolds by Stahura et al [41]. For scaffold comparison, we have looked at both the coverage of the benchmark scaffolds by VER_ref as well as the breadth or density of coverage (proportion of VER_ref library containing such scaffolds).…”

Section: Comparison To the Published Scaffoldsmentioning

confidence: 99%

Lessons for fragment library design: analysis of output from multiple screening campaigns

Chen¹,

Hubbard

2009

J Comput Aided Mol Des

116

105

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Over the past 8 years, we have developed, refined and applied a fragment based discovery approach to a range of protein targets. Here we report computational analyses of various aspects of our fragment library and the results obtained for fragment screening. We reinforce the finding of others that the experimentally observed hit rate for screening fragments can be related to a computationally defined druggability index for the target. In general, the physicochemical properties of the fragment hits display the same profile as the library, as is expected for a truly diverse library which probes the relevant chemical space. An analysis of the fragment hits against various protein classes has shown that the physicochemical properties of the fragments are complementary to the properties of the target binding site. The effectiveness of some fragments appears to be achieved by an appropriate mix of pharmacophore features and enhanced aromaticity, with hydrophobic interactions playing an important role. The analysis emphasizes that it is possible to identify small fragments that are specific for different binding sites. To conclude, we discuss how the results could inform further development and improvement of our fragment library.

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Section: Comparison To the Published Scaffoldsmentioning

confidence: 99%

Lessons for fragment library design: analysis of output from multiple screening campaigns

Chen¹,

Hubbard

2009

J Comput Aided Mol Des

116

105

View full text Add to dashboard Cite

show abstract

“…Often, such scaffolds may be chemically related to endogenous ligands for particular protein classes. Recent examples of focused libraries include those targeted against G-protein coupled receptors (GPCRs) 13 , proteases 14 , phosphatases 15 and kinases 16 . In contrast, diversity-oriented libraries are not targeted to any specific protein class and are often used in broad screens in which the target proteins are not known.…”

Section: Assembling the 'Ideal' Chemical Librarymentioning

confidence: 99%

Exploring biology with small organic molecules

Stockwell

2004

Nature

434

307

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Small organic molecules have proven to be invaluable tools for investigating biological systems, but there is still much to learn from their use. To discover and to use more effectively new chemical tools to understand biology, strategies are needed that allow us to systematically explore 'biological-activity space'. Such strategies involve analysing both protein binding of, and phenotypic responses to, small organic molecules. The mapping of biological-activity space using small molecules is akin to mapping the stars--uncharted territory is explored using a system of coordinates that describes where each new feature lies.

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“…Docking and scoring is another SBDD approach, which is very similar to ligand-based library design, except that biostructural information is used to select suitable compounds for synthesis from an enumerated virtual library. Typically, structures that pass property filters are sequentially docked into the ligand-binding site and prioritized on the basis of their docking scores [79,80]. For general docking and scoring methods and their applications for structurebased virtual screening see Chapter 3.…”

Section: Screening Collection Enhancement Strategiesmentioning

confidence: 99%