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Molecular fingerprints are not useful in large-scale search for similarly active compounds†

View ORCID ProfileVishwesh Venkatraman, Jeremiah Gaiser, Amitava Roy, View ORCID ProfileTravis J. Wheeler
doi: https://doi.org/10.1101/2022.09.20.508800
Vishwesh Venkatraman
aNorwegian University of Science and Technology, Department of Chemistry, 7491 Trondheim, Norway. E-mail:
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  • For correspondence: vishwesh.venkatraman@ntnu.no vishwesh.venkatraman@ntnu.no
Jeremiah Gaiser
bDepartment of Computer Science, University of Montana, Missoula, MT, USA
cDepartment of Biochemistry and Biophysics, University of Montana, Missoula, MT, USA
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Amitava Roy
dBioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA
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Travis J. Wheeler
bDepartment of Computer Science, University of Montana, Missoula, MT, USA
eDepartment of Pharmacy Practice and Science, University of Arizona, Tucson, AZ, USA
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Abstract

Computational approaches for small molecule drug discovery now regularly scale to consideration of libraries containing billions of candidate small molecules. One promising path to increased speed in evaluating billion-molecule libraries is to develop representations of each molecule that enable fast computation of similarity between molecules. Molecular fingerprints have long provided a mechanism for succinct representation and fast comparison of small molecules, with a large collection of competing fingerprints. Here, we explore the utility of many of these fingerprints in the context of predicting similar molecular activity. We show that fingerprint similarity enables insufficient discriminative power between active and inactive molecules for a target protein based on a known active. We also demonstrate that, even when limited to only active molecules, fingerprint similarity values do not correlate with compound potency. In sum, these results highlight the need for a new wave of molecular representations that will improve the capacity to detect biologically active molecules based on similarity to other such molecules.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • † Electronic Supplementary Information (ESI) available. See DOI: 00.0000/00000000.

  • https://osf.io/d3cbr/

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted September 22, 2022.
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Molecular fingerprints are not useful in large-scale search for similarly active compounds†
Vishwesh Venkatraman, Jeremiah Gaiser, Amitava Roy, Travis J. Wheeler
bioRxiv 2022.09.20.508800; doi: https://doi.org/10.1101/2022.09.20.508800
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Molecular fingerprints are not useful in large-scale search for similarly active compounds†
Vishwesh Venkatraman, Jeremiah Gaiser, Amitava Roy, Travis J. Wheeler
bioRxiv 2022.09.20.508800; doi: https://doi.org/10.1101/2022.09.20.508800

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