Volume 5 Supplement 1

8th German Conference on Chemoinformatics: 26 CIC-Workshop

Open Access

Annotating targets with pathways: extending approaches to mode of action analysis

  • Sonia Liggi1,
  • Alexios Koutsoukas1,
  • Yasaman Kalantar Motamedi1,
  • Robert C Glen1 and
  • Andreas Bender1Email author
Journal of Cheminformatics20135(Suppl 1):P15

DOI: 10.1186/1758-2946-5-S1-P15

Published: 22 March 2013

When attempting to treat pathological conditions, it is often necessary to act on multiple targets in order to modify the implicated biological network(s). A systems biology approach would help the drug discovery field by providing a link between chemistry and biology [1]. In particular, annotation of targets with pathways would allow a better understanding of a drug mechanism of action, side effects [2] and promiscuity [3], as well as complex network modulation [4]. A deep understanding of these factors is fundamental to design a drug with the desired pharmacological profile against multiple targets and, to the extent possible, to avoid side effects.

In this context, a cheminformatics target prediction tool [5] was used on several small molecule phenotypic datasets (such as cytotoxicity), and the predicted targets were annotated with the pathways they belong to. Predicted targets and annotated pathways were subjected to an enrichment calculation in order to eliminate the prediction noise and highlight only those likely to be implicated in the phenotype studied. Several enrichment methods were tested and compared, leading to the conclusion that there is not a single method that stands out, but instead the combination of several methods is needed to increase the significance of the readouts.

This protocol allowed us to highlight pathways implicated in the analysed phenotypes which would not be identified by considering only predicted targets, hence giving further insight into the mechanism of expression of the observed phenotype.

Authors’ Affiliations

(1)
Unilever Centre for Molecular Informatics, Department of Chemistry, University of Cambridge

References

  1. Hood L, et al: The impact of systems approaches on biological problems in drug discovery. Nature Biotechnol. 2004, 22: 1215-1217. 10.1038/nbt1004-1215.View ArticleGoogle Scholar
  2. Scheiber J, et al: Gaining insight into off- target mediated effects of drug candidates with a comprehensive systems chemical biology analysis. J Chem Inf Model. 2009, 49: 308-317. 10.1021/ci800344p.View ArticleGoogle Scholar
  3. Hettne K, et al: Connecting small molecules to nuclear receptor pathways. Curr Top Med Chem. 2007, 7: 1530-1536. 10.2174/156802607782194671.View ArticleGoogle Scholar
  4. Xie L, et al: Drug discovery using chemical systems biology: identification of the protein- ligand binding network to explain the side effects of CETP inhibitors. PLoS Computational Biology. 2009, 5: e1000387-10.1371/journal.pcbi.1000387.View ArticleGoogle Scholar
  5. Koutsoukas A, et al: In silico target predictions: comparing multiclass Naïve Bayes and Parzen-Rosenblatt Window and the definition of a benchmarking dataset for target prediction. In preparation.Google Scholar

Copyright

© Liggi et al.; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.