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Metabolomics. 2015;11(2):323-339. Epub 2014 Sep 19.

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

Author information

1
School of Chemistry, The University of Manchester, 131 Princess St, Manchester, M1 7DN UK ; The Manchester Institute of Biotechnology, The University of Manchester, 131 Princess St, Manchester, M1 7DN UK.
2
The Manchester Institute of Biotechnology, The University of Manchester, 131 Princess St, Manchester, M1 7DN UK ; School of Computer Science, The University of Manchester, 131 Princess St, Manchester, M1 7DN UK.
3
Manchester Business School, The University of Manchester, 131 Princess St, Manchester, M1 7DN UK.

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.

KEYWORDS:

Cheminformatics; Drug-likeness; Genome-wide metabolic reconstruction; KNIME; Metabolite-likeness; Recon 2

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