Drug target identification and mode of action studies for molecules discovered through phenotypic screens usually represent a bottleneck in drug discovery. The limited abundance of compound available for characterization studies is an additional fundamental concern in natural products drug discovery, particularly if the structural complexity precludes chemical synthesis in a timely manner. Genomic and proteomic profiling techniques which require only minute amounts of natural products are being applied in our lab to gain insight into how the compounds act globally on the molecular and cellular level. We systematically transfer genome-wide studies used in yeast to infer targets of bioactive compounds into more relevant mammalian systems in order to interrogate more complex pathways. Specifically, we use chemogenomic profiling in yeast as well as RNAi-based drug susceptibility screens in mammalian cells to identify pathways that are modulated by the compound. We use classical biochemical approaches to study affected molecular pathways and to validate hypotheses derived from global strategies.
The CNPD3 partners with a commercial laboratory that has the ability to screen across hundreds of receptors, and these preliminary data guide follow up hits to be interrogated in CNPD3 laboratories.