"From Cations to Small Molecules: An Atomic-Level Understanding of How to Fine-Tune m-Opioid Receptor Signaling for the Development of Safer Opioid Therapies"

Marta Filizola, Ph.D. Graduate School of Biomedical Sciences Dean and Professor With an average of 130 Americans dying every day, and opioid drugs still representing the gold standard for pain management, there is an urgent need to identify innovative solutions to prevent life-threatening opioid overdoses and treat opioid use disorders. Clinical opioid drugs inhibit nociceptive signaling but also cause respiratory depression by targeting a G-protein coupled receptor, specifically the µ-opioid receptor (MOPr) subtype. An atomic-level understanding of the molecular mechanisms at the basis of this diversity of MOPr signaling is essential for discovering analgesics with reduced adverse effects. This presentation includes an overview of recent studies we have carried out in the lab using enhanced molecular dynamics simulations in combination with Markov state models, information theory and/or machine learning analyses to investigate how different cations and small molecules specifically modulate the conformational plasticity of MOPr, with the ultimate goal of understanding how to fine-tune opioid receptor signaling toward desired therapeutic pathways and away from those regulating adverse effects.