Project Summary/Abstract The hundreds of different bioactive components in the venoms of cone snails have demonstrated extraordinary biomedical potential in the past, including development as an FDA-approved drug. However, their discovery and characterization is generally limited by the small amounts of venom that are accessible. Our laboratory has developed a calcium-imaging platform combined with selective pharmacology (“Constellation Pharmacology”), that when combined with recent technical advances in transcriptomic and proteomic analysis and electrophysiology (an integrated platform that we call Pharmaconomics) completely changes the landscape with respect to discovery and characterization of novel venom components. Using pharmaconomics, one goal is to tightly couple the discovery and biochemical characterization of individual venom components with the elucidation of the molecular and cellular mechanisms that underlie their biological activity. The pharmaconomics approach also uncovers how individual components affect physiology at the system’s and whole animal level. We will use the insights gained from the characterization of bioactive venom components to rationalize the species-specific behavior and neuroethology of the cone snail and it’s fish prey. These new tools should allow an unprecedented rate of discovery of novel bioactive cone snail venom components tightly linked to the elucidation of their molecular targets. Although the focus of this project is on venom peptides and their molecular targets, the pharmaconomics approach can be used for elucidating the physiologically-relevant molecular target of any natural product. Linking the vast chemical diversity of natural products to their cognate macromolecular receptors should greatly expand the use of natural products as pharmacological tools in basic research, as well as their therapeutic and other biomedical applications.