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Toxicogenomics screening of small molecules using high-density, nanocapillary real-time PCR
Laura Vass1, János Z Kelemen, Liliána Z Fehér
1Laboratory of Functional Genomics, Biological Research Center of the Hungarian Academy of Sciences, 6726 Szeged, Hungary.
International Journal of Molecular Medicine
|December 17, 2008
Summary
Structurally different compounds can exhibit similar toxicity profiles by altering gene expression. However, compounds with the same molecular structure do not always share similar biological effects, challenging the generalized neighborhood behavior concept.
Area of Science:
- Toxicogenomics
- Computational chemistry
- Molecular toxicology
Background:
- Compounds inducing toxicity via similar mechanisms produce characteristic gene expression patterns.
- Demonstrating generalized neighborhood behavior (structurally similar compounds having similar biological profiles) is challenging.
Purpose of the Study:
- To investigate the correlation between molecular structure and biological fingerprint using gene expression profiles.
- To assess the generalized neighborhood behavior in a large compound library.
Main Methods:
- Screened 625 compounds from a combinatorial library for gene expression profiles.
- Utilized nanocapillary quantitative real-time PCR OpenArray technology for medium-throughput analysis.
- Applied hybrid clustering to gene expression data to correlate molecular scaffold with biological fingerprint.
Main Results:
- Structurally dissimilar compounds with similar hepatotoxicity showed comparable gene expression fingerprints.
- Compounds sharing the same scaffold did not consistently exhibit similar biological effects based on gene expression.
- Out of 12 scaffolds, 8 showed neighborhood behavior, while 4 did not correlate with clusters.
Conclusions:
- Biological activity, particularly toxicity, is not solely dictated by molecular structure.
- Gene expression profiling can reveal functional similarities between structurally diverse compounds.
- The generalized neighborhood behavior is not universally applicable, especially for compounds with unknown biological effects.
