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Bioinformatics Advance Access published online on September 10, 2008
Bioinformatics, doi:10.1093/bioinformatics/btn479
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© The Author (2008). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Chemical Substructures that Enrich for Biological Activity

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

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

*To whom correspondence should be addressed. Frederick P. Roth, E-mail: froth{at}hms.harvard.edu


  Abstract

Motivation: Certain chemical substructures are present in many drugs. This has led to the claim of "privileged" substructures which are pre-disposed to bioactivity. Because bias in screening library construction could explain this phenomenon, the existence of privi-lege has been controversial. Using diverse phenotypic assays, we defined bioactivity for multiple compound libraries. Many substruc-tures 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.

Associate Editor: Dr. Jonathan Wren

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

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