Dataset Information

Understanding the foundations of the structural similarities between marketed drugs and endogenous human metabolites.

ABSTRACT: 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.

SUBMITTER: O'Hagan S

PROVIDER: S-EPMC4429554 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Understanding the foundations of the structural similarities between marketed drugs and endogenous human metabolites.

O'Hagan Steve S Kell Douglas B DB

Frontiers in pharmacology 20150513

<h4>Background</h4>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").<h4>Results</h4>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 ...[more]

PMID: 26029108

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Project description:BackgroundPrevious studies compared the molecular similarity of marketed drugs and endogenous human metabolites (endogenites), using a series of fingerprint-type encodings, variously ranked and clustered using the Tanimoto (Jaccard) similarity coefficient (TS). Because this gives equal weight to all parts of the encoding (thence to different substructures in the molecule) it may not be optimal, since in many cases not all parts of the molecule will bind to their macromolecular targets. Unsupervised methods cannot alone uncover this. We here explore the kinds of differences that may be observed when the TS is replaced-in a manner more equivalent to semi-supervised learning-by variants of the asymmetric Tversky (TV) similarity, that includes ? and ? parameters.ResultsDramatic differences are observed in (i) the drug-endogenite similarity heatmaps, (ii) the cumulative "greatest similarity" curves, and (iii) the fraction of drugs with a Tversky similarity to a metabolite exceeding a given value when the Tversky ? and ? parameters are varied from their Tanimoto values. The same is true when the sum of the ? and ? parameters is varied. A clear trend toward increased endogenite-likeness of marketed drugs is observed when ? or ? adopt values nearer the extremes of their range, and when their sum is smaller. The kinds of molecules exhibiting the greatest similarity to two interrogating drug molecules (chlorpromazine and clozapine) also vary in both nature and the values of their similarity as ? and ? are varied. The same is true for the converse, when drugs are interrogated with an endogenite. The fraction of drugs with a Tversky similarity to a molecule in a library exceeding a given value depends on the contents of that library, and ? and ? may be "tuned" accordingly, in a semi-supervised manner. At some values of ? and ? drug discovery library candidates or natural products can "look" much more like (i.e., have a numerical similarity much closer to) drugs than do even endogenites.ConclusionsOverall, the Tversky similarity metrics provide a more useful range of examples of molecular similarity than does the simpler Tanimoto similarity, and help to draw attention to molecular similarities that would not be recognized if Tanimoto alone were used. Hence, the Tversky similarity metrics are likely to be of significant value in many general problems in cheminformatics.

Dataset Information

Understanding the foundations of the structural similarities between marketed drugs and endogenous human metabolites.

Publications

Understanding the foundations of the structural similarities between marketed drugs and endogenous human metabolites.

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