Determination of minimal transcriptional signatures of compounds for target prediction

Early drug discovery research involves target discovery and lead discovery. Target discovery is concerned with the identification and validation of the disease-relevance of a particular protein. Subsequent lead discovery is the task of finding a suitable molecule that can interact with the target in a specific, therapeutically relevant way. A typical strategy to identify potential lead compounds is the screening of large collections of molecules, up to several millions, in highly automated high-throughput assays. In biochemical assays, each molecule is tested against a purified target protein of interest; molecules that are found to significantly affect the assay readout are called hits and are selected for further follow-up experiments such as secondary- or counter-screens. Successful outcomes in those latter screens result in more confidence of having found a true modulator of the target protein, yielding a target-lead pair. An orthogonal approach where the target protein is unknown from the outset is a phenotypic screen: a collection of molecules is tested for their potential to induce (or abrogate) a complex phenotype, such as the ability of cells to divide successfully. Because the target protein of such screens is not known, they require the identification of the target that gives rise to the observed phenotype subsequent to the identification of active compounds.Whereas biochemical assays have the advantage that the target protein is essentially a parameter of the experiment, they often lack biological relevance because compounds tested do not have to penetrate cell walls and are not subjected to other relevant biological processes such as active transport and metabolism. Phenotypic assays are a more realistic model for compound administration to living systems but entail the significant post-screen difficulty of target identification and mode of action (MoA) elucidation for any hits identified.The identification of molecular target and MoA of compounds is a