A 'rule of 0.5' for the metabolite-likeness of approved pharmaceutical drugs

Metabolomics : Official Journal of the Metabolomic Society
Steve O HaganDouglas B Kell

Abstract

We exploit the recent availability of a community reconstruction of the human metabolic network ('Recon2') to study how close in structural terms are marketed drugs to the nearest known metabolite(s) that Recon2 contains. While other encodings using different kinds of chemical fingerprints give greater differences, we find using the 166 Public MDL Molecular Access (MACCS) keys that 90 % of marketed drugs have a Tanimoto similarity of more than 0.5 to the (structurally) 'nearest' human metabolite. This suggests a 'rule of 0.5' mnemonic for assessing the metabolite-like properties that characterise successful, marketed drugs. Multiobjective clustering leads to a similar conclusion, while artificial (synthetic) structures are seen to be less human-metabolite-like. This 'rule of 0.5' may have considerable predictive value in chemical biology and drug discovery, and may represent a powerful filter for decision making processes.

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Citations

Mar 1, 2016·Trends in Pharmacological Sciences·Pedro MendesDouglas B Kell
Aug 4, 2016·Journal of Chemical Information and Modeling·Shardul ParicharakFlorian Nigsch
Oct 4, 2016·Metabolomics : Official Journal of the Metabolomic Society·Douglas B Kell, Stephen G Oliver
Oct 24, 2019·American Journal of Physical Anthropology·Cecil M LewisPaul G Spicer
Feb 14, 2020·Nutrition Research Reviews·Irina BorodinaDouglas B Kell
Mar 21, 2017·Journal of Cheminformatics·Steve O'Hagan, Douglas B Kell
May 2, 2018·Biotechnology Journal·Roland Wohlgemuth
Aug 6, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Soumitra SamantaDouglas B Kell
Sep 6, 2019·Pharmaceutical Frontiers·Steve O'Hagan, Douglas B Kell
Jun 27, 2019·Journal of Cheminformatics·Jeremy R AshDenis Fourches
May 1, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Aditya Divyakant Shrivastava, Douglas B Kell
Jun 27, 2018·Molecular Pharmaceutics·David DickensAnne T Nies
Jan 19, 2020·Biotechnology Advances·Divya AroraSamuel Bertrand

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Software Mentioned

StreptomedB
MOCK
Excel
Open Babel
Recon2
Taverna
KNIME
libAnnotationSBML Development Kit
R
CDK

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