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Chemical substructures that enrich for biological activity
Open accessAbstract
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.
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“To bypass the limitations of MS/MS spectral libraries, an alternative computational approach translates MS/MS information directly into structural information as structural fingerprints.163”
From Connecting metabolome and phenotype: recent advances in functional metabolomics tools for the identification of bioactive natural products (2024) · cites this paper as [163]
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Metadata
- Authors
- Klekota, J., & Roth, F. P.
- Affiliations
- Harvard University (US)
- Corresponding author
- Roth, Frederick P.
- ORCID
- Roth, Frederick P.
- Venue
- Bioinformatics
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-09-11
- Volume
- 24
- Issue
- 21
- Pages
- 2518-2525
- ISSN
- 1367-4803 (ISSN-L)
- 1367-4811
- PMC
- PMC2732283
- OpenAlex
- W2107081909
- Cited by
- 392
- References
- 62
- Citations by year
- 2026: 27 · 2025: 28 · 2024: 43 · 2023: 37 · 2022: 24 · 2021: 22 · 2020: 22 · 2019: 18 · 2018: 34 · 2017: 27 · 2016: 31 · 2015: 22 · 2014: 17 · 2013: 13 · 2012: 14
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Bioinformatics (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- Centre National de la Recherche Scientifique
- National Institute on Aging (R01AG017115)
- National Heart, Lung, and Blood Institute (U01HL081341)
- National Human Genome Research Institute (R01 HG0017115, R01HG003224, P50HG004233)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and Characterization of Heterocyclic Compounds
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Keywords
- chemical substructures, bioactivity prediction, chemical libraries, phenotypic assays, aromatic ring systems, drug discovery, structure-activity relationship
- MeSH terms
- Animals, Cells, Cultured, Pharmaceutical Preparations, Humans, Ligands, Structure-Activity Relationship, Drug Design, Databases, Factual, Combinatorial Chemistry Techniques
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