About 11-40% of US adults suffer from chronic pain, which is often treated with opioids. Because of frequent opioid misuse, alternative approaches to pain management are desperately needed. Recent studies have suggested that positive allosteric modulators (PAMs) of glycine receptors (GlyRs) are potential non-opioid analgesic alternatives. Tetrahydrocannabinol (THC), an active ingredient in marijuana, was found to be a GlyR PAM. Early experiments discovered a series of molecules with potential affinity for the THC binding site, but their potency and efficacy as GlyR PAMs have not been fully explored. Here, we used weighted ensemble (WE) simulations to study the impact of modulator binding (potency) to the THC binding site and the induced conformational changes to the ion channel function (efficacy). A hydrated membrane patch containing an α3 GlyR structure with THC in the experimentally suggested binding pocket was created to test THC binding stability and analyze the induced conformational changes in the system. Subsequent molecular dynamics (MD) simulations of the α3 GlyR with other PAM candidates were carried out to determine the optimal interactions to establish a correlation between potency and efficacy. Our results offer a structural understanding of the α3 GlyR modulation and a targeted approach to identifying new, potentially better GlyR PAMs for pain treatment.

Evaluating positive-allosteric-modulator-induced conformational changes of α3 glycine receptor

Where thousands of chemistry professionals meet to share ideas and advance scientific and technical knowledge. Spring 2023 abstracts, posters, and presentations will launch at the end of March.

ACS Spring 2023

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.