Developing Tools to Facilitate Dynamics-Based Drug Discovery of Receptors of Drugs of Abuse

Project Summary/Abstract Many drugs of abuse target G protein coupled receptors (GPCRs), including the opioids which have fueled the ongoing opioid abuse epidemic. Many of these compounds have substantial room for improving their therapeutic window by precisely tuning their signaling profiles. However, rational design of such compounds is difficult due to a lack of understanding of how these compounds alter the structure and dynamics of receptors to relay their pharmacological profile intracellularly to their signaling partners. Here we propose to generate chemical biology tools to facilitate the determination of molecular movies of GPCRs interacting with their signaling partners with time-resolved cryogenic electron microscopy. This will be complemented by the development of a new computational method to drive simulations from time-resolved cryogenic electron microscopy data in order to fully sample all of the transition and intermediate states involved in GPCR signaling. These methods will be applied to several ligands of various efficacies for a key receptor for drugs of abuse, and the insights used in ultra-high throughput virtual screening campaigns to identify novel allosteric modulations to stabilize specific intermediate states. Finally, allosteric compounds will be tested in rodent models of addiction to explore how modulation of these specific intermediate states attenuates the addiction liability of canonical drugs of abuse.