Understanding the foundations of the structural similarities between marketed drugs and endogenous human metabolites
Steve O'Hagan1, Douglas B Kell1
1School of Chemistry, The University of Manchester Manchester, UK ; The Manchester Institute of Biotechnology, The University of Manchester Manchester, UK.
Background:
A recent comparison showed the extensive similarities between the structural properties of metabolites in the reconstructed human metabolic network ("endogenites") and those of successful, marketed drugs ("drugs").
Results:
Clustering indicated the related but differential population of chemical space by endogenites and drugs. Differences between the drug-endogenite similarities resulting from various encodings and judged by Tanimoto similarity could be related simply to the fraction of the bitstrings set to 1. By extracting drug/endogenite substructures, we develop a novel family of fingerprints, the Drug Endogenite Substructure (DES) encodings, based on the ranked frequency of the various substructures. These provide a natural assessment of drug-endogenite likeness, and may be used as descriptors with which to derive quantitative structure-activity relationships (QSARs).
Conclusions:
"Drug-endogenite likeness" seems to have utility, and leads to a simple, novel and interpretable substructure-based molecular encoding for cheminformatics.
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