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Bioinformatics Advance Access originally published online on September 10, 2008
Bioinformatics 2008 24(21):2518-2525; doi:10.1093/bioinformatics/btn479
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Chemical substructures that enrich for biological activity

Justin Klekota 1,2 and Frederick P. Roth 3,4,*

1Harvard University Graduate Biophysics Program, Harvard Medical School, 250 Longwood Avenue, 2Harvard Institute of Chemistry and Cell Biology, 3Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue and 4Center for Cancer Systems Biology, Dana-Farber Cancer Institute, One~Jimmy Fund Way, Boston, MA 02115, USA

*To whom correspondence should be addressed.


  Abstract

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{at}hms.harvard.edu

Supplementary information: Supplementary data are available at Bioinformatics online.

Associate Editor: Jonathan Wren

Received on May 6, 2008; revised on August 13, 2008; accepted on September 7, 2008

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