Molecular Details of Psychoactive Drug Actions

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PROJECT SUMMARY: Scientific summary: The 5-HT2-serotonin family of receptors represents essential drug targets for most atypical antipsychotics as well as drugs useful in treating obesity, sleep disorders, psychosis and autistic- spectrum disorders. It is currently unknown how these drugs interact with their target receptors. Here we aim to obtain high resolution structures of 5-HT2-family receptors bound to various transducers (G proteins and arrestins) and biased and unbiased agonists. We will use these structures to prosecute ultra-large-scale docking campaigns (up to 15 billion novel compounds) to discover improved chemical tools for these receptors. These studies are both innovative technically and conceptually by providing an unprecedented understanding of the molecular and atomic details responsible for psychoactive drug actions. Additionally, models which attempt to explain ligand-specific properties of biased signaling from the perspective of ligand-receptor interactions will be tested by a combination of direct structural studies, molecular modeling, docking, site-directed mutagenesis and functional studies. We anticipate that our studies will reveal key ligand-receptor interactions essential for biased signaling for serotonin receptors. Elucidating the molecular details for such interactions provides a template for the structure-guided design of novel therapeutics.