Journal Article

Chemical substructures that enrich for biological activity

Justin Klekota and Frederick P. Roth

in Bioinformatics

Volume 24, issue 21, pages 2518-2525
Published in print November 2008 | ISSN: 1367-4803
Published online September 2008 | e-ISSN: 1460-2059 | DOI: http://dx.doi.org/10.1093/bioinformatics/btn479

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Motivation: Certain chemical substructures are present in many drugs. This has led to the claim of ‘privileged’ substructures which are predisposed to bioactivity. Because bias in screening library construction could explain this phenomenon, the existence of privilege has been controversial.

Results: Using diverse phenotypic assays, we defined bioactivity for multiple compound libraries. Many substructures were associated with bioactivity even after accounting for substructure prevalence in the library, thus validating the privileged substructure concept. Determinations of privilege were confirmed in independent assays and libraries. Our analysis also revealed ‘underprivileged’ substructures and ‘conditional privilege’—rules relating combinations of substructure to bioactivity. Most previously reported substructures have been flat aromatic ring systems. Although we validated such substructures, we also identified three-dimensional privileged substructures. Most privileged substructures display a wide variety of substituents suggesting an entropic mechanism of privilege. Compounds containing privileged substructures had a doubled rate of bioactivity, suggesting practical consequences for pharmaceutical discovery.

Contact: fritz_roth@hms.harvard.edu

Supplementary information: Supplementary data are available at Bioinformatics online.

Journal Article.  5733 words.  Illustrated.

Subjects: Bioinformatics and Computational Biology

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