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Bioinformatics. 2008 Nov 1;24(21):2518-25. doi: 10.1093/bioinformatics/btn479. Epub 2008 Sep 10.

Chemical substructures that enrich for biological activity.

Author information

1
Harvard University Graduate Biophysics Program, Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115, USA.

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.

PMID:
18784118
PMCID:
PMC2732283
DOI:
10.1093/bioinformatics/btn479
[Indexed for MEDLINE]
Free PMC Article

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