TY - JOUR
AU - Roth, Frederick P.
AB - 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.eduSupplementary information: Supplementary data are available at Bioinformatics online.
TI - Chemical substructures that enrich for biological activity
JF - Bioinformatics
DO - 10.1093/bioinformatics/btn479
DA - 2008-09-11
UR - https://www.deepdyve.com/lp/oxford-university-press/chemical-substructures-that-enrich-for-biological-activity-t90siU0YVe
SP - 2518
EP - 2525
VL - 24
IS - 21
DP - DeepDyve
ER -