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Cited by 5Computational Drug Discovery MethodsPharmacogenetics and Drug MetabolismAnimal testing and alternatives

The missing enzymes: a call to update pharmacological profiling practices for better drug safety assessment

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Maciag, Monika, Karamyan, Vardan T.·2025·Journal of Medicinal Chemistry
DOI 10.1021/acs.jmedchem.4c02228PMC PMC12035801
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Abstract

Pharmacological profiling is critical for the development of safe drugs. With increasing awareness of its significance and attempts to share best practices, here we aimed to understand how pharmacological profiling is implemented and reported in the primary literature by analyzing the representation of nonkinase enzymes in selectivity screens. This aspect has been overlooked in previous publications, despite enzymes constituting a significant portion of the pharmacological targets for currently marketed drugs. Our analysis shows that while industry recommendations for improved pharmacological profiling have been widely adopted, enzymes remain largely underrepresented: about a quarter of studies did not include enzymes, and on average, enzymes comprise only 11% of all targets in pharmacological screens. We discuss possible reasons for this shortcoming and provide examples of critical enzymes missing from current screens. We conclude with the notion that selectivity screens should be expanded to include more enzymes to improve drug development and safety.

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Cited by

Sorted by citations

Authors
Maciag, M., & Karamyan, V. T.
Affiliations
  • Department of Foundational Medical Studies, William Beaumont School of Medicine
  • Oakland University (US)
Corresponding author
Karamyan, Vardan T.
ORCID
Karamyan, Vardan T.
Venue
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Published
2025-04-02
Volume
68
Issue
8
Pages
7854-7865
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
DOI
10.1021/acs.jmedchem.4c02228
PMC
PMC12035801
OpenAlex
W4409091135
Cited by
5
References
5
Citations by year
2026: 3 · 2025: 2
FWCI
0.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Medicinal Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
U.S. Department of Health and Human Services (R01NS106879)
Topics
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
Keywords
drug profiling, drug safety assessment, drug-likeness
MeSH terms
Animals, Drug Evaluation, Preclinical, Enzymes, Humans

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Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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