Chemical substructures that enrich for biological activity

Klekota, Justin; Roth, Frederick P.

doi:10.1093/bioinformatics/btn479

Cited by 394Computational Drug Discovery MethodsSynthesis and Characterization of Heterocyclic CompoundsChemical Synthesis and Analysis

Chemical substructures that enrich for biological activity

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Klekota, Justin, Roth, Frederick P.·2008·Bioinformatics

DOI 10.1093/bioinformatics/btn479PMC PMC2732283

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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@hms.harvard.edu Supplementary information: Supplementary data are available at Bioinformatics online.

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An alternative computational approach translates MS/MS information directly into structural information as structural fingerprints.
“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]
Methods §2.2 describes binary arrays recording the presence or absence of chemical substructures, which are structural fingerprints. But those arrays are generated from known compound structures, not MS/MS information; the passage does not support the claim that this approach bypasses spectral libraries. (LLM, conf=0.83)
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Data and text mining Chemical substructures that enrich for biological activity
Klekota, J., & Roth, F. P. (2016)
Self-citation
Privilegierte Strukturen neu betrachtet
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Statistical investigation of the data file on biologically active compounds. V. Allowance for the novelty of the chemical structure in the prediction of the biological activity by an improved method of substructural analysis
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Privileged Structures: Applications in Drug Discovery
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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
DOI: 10.1093/bioinformatics/btn479
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: cc-by-nc
creativecommons.org/licenses/by-nc/2.0/uk/ (vor, 2943 d)
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: Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
Physical Sciences › Chemistry › Organic Chemistry › Synthesis and Characterization of Heterocyclic Compounds
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 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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Chemical substructures that enrich for biological activity

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