Abstract

We developed an extensive yeast gene expression library consisting of full-genome cDNA array data for over 500 yeast strains, each with a single-gene disruption. Using this data, combined with dose and time course expression experiments with the oral antifungal agent griseofulvin, whose exact molecular targets were previously unknown, we used Boolean and Bayesian network discovery techniques to determine the gene expression regulatory cascades affected directly by this drug. Using this method we identified CIK1 as an important affected target gene related to the functional phenotype induced by griseofulvin. Cellular functional analysis of griseofulvin showed similar tubulin-specific morphological effects on mitotic spindle formation to those of the drug, in agreement with the known function of CIK1p. Further, using the nonparametric, nonlinear Bayesian gene networks we were able to identify alternative ligand-dependant transcription factors and G protein homologues upstream of CIK1 that regulate CIK1 expression and might therefore serve as alternative molecular targets to induce the same molecular response as griseofulvin. Key words: drug discovery; microarray; CIK1; griseofulvin; network Rational drug design methodologies have previously been concentrated on optimizing small molecules against

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