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Analysis of drug-induced effect patterns to link structure and side effects of medicines

Nature Chemical Biology volume 1, pages 389–397 (2005)Cite this article

Abstract

The high failure rate of experimental medicines in clinical trials accentuates inefficiencies of current drug discovery processes caused by a lack of tools for translating the information exchange between protein and organ system networks. Recently, we reported that biological activity spectra (biospectra), derived from in vitro protein binding assays, provide a mechanism for assessing a molecule's capacity to modulate the function of protein-network components. Herein we describe the translation of adverse effect data derived from 1,045 prescription drug labels into effect spectra and show their utility for diagnosing drug-induced effects of medicines. In addition, notwithstanding the limitation imposed by the quality of drug label information, we show that biospectrum analysis, in concert with effect spectrum analysis, provides an alignment between preclinical and clinical drug-induced effects. The identification of this alignment provides a mechanism for forecasting clinical effect profiles of medicines.

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Figure 1: Classification of side effect information for 1,045 medicines.
Figure 2: Comparison of preclinical and clinical drug-induced effect similarity of 40 medicines.
Figure 3: Comparison of biospectra and effect spectra of 19 sedative-hypnotic medicines.
Figure 4: Association between biospectral and side effect similarity for 25 medicines: an independent assessment of similarity distance relationships between side-effect and biospectral profile similarity for compounds in the 872-medicine database.

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Acknowledgements

The authors would like to thank D.M. Potter for useful discussions.

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Authors and Affiliations

  1. Pfizer Global Research and Development, Eastern Point Road, Groton, 06340, Connecticut, USA

    Anton F Fliri, William T Loging, Peter F Thadeio & Robert A Volkmann

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  1. Anton F Fliri
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  2. William T Loging
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  3. Peter F Thadeio
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  4. Robert A Volkmann
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Corresponding authors

Correspondence to Anton F Fliri or Robert A Volkmann.

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Supplementary information

Supplementary Fig. 1

The experimental design for investigating the information exchange between drug-induced protein network perturbations to drug-induced organ systems perturbations. (PDF 148 kb)

Supplementary Fig. 2

Positions of ninety-two protein assays in the mammalian proteome network. (PDF 3113 kb)

Supplementary Fig. 3

Sedative-hypnotic cluster. (PDF 718 kb)

Supplementary Fig. 4

Side effect distances compared to BioSpectra distances. (PDF 228 kb)

Supplementary Table 1

List of ninety-two assays. (PDF 50 kb)

Supplementary Table 2

List of 872 medicines. (PDF 48 kb)

Supplementary Table 3

ADRS. (PDF 42 kb)

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Fliri, A., Loging, W., Thadeio, P. et al. Analysis of drug-induced effect patterns to link structure and side effects of medicines. Nat Chem Biol 1, 389–397 (2005). https://doi.org/10.1038/nchembio747

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