BPS2026 – Application of molecular dynamics for development of therapeutics against opioid overdose

Opioid overdose is a long-standing public health issue in the United States, which has only been exacerbated by the Covid-19 pandemic, with overdose deaths involving opioids increasing from an estimated 70,630 in 2019 to 107,941 in 2022. While there are treatments for opioid overdose, currently no therapeutic tools exist to prevent it. Moreover, treatments such as naloxone are limited to emergency scenarios because they induce withdrawal and loss of analgesia. Fatal opioid overdoses are primarily attributed to opioid-induced respiratory depression (OIRD). As part of an ongoing collaboration, a class of cysteine derivatives has been identified that reverse OIRD without blocking analgesic effects or inducing withdrawal. The current hypothesis is that the cysteine derivatives function by binding β-arrestin, a downstream signaling partner of opioid receptors. The goal of my proposed work is to characterize this binding interaction to rationalize the trends observed in the preliminary data. Using molecular dynamics-based methods, I have identified unique potential binding sites for some members of this class of compounds to the inactive structures of β-arrestin 1 and β-arrestin 2. I am using alchemical free-energy calculations to determine the affinity of the candidate binding sites; the results will be tested experimentally by collaborators using surface plasmon resonance and hydrogen-deuterium mass spectroscopy. Additionally, experimental data show super-additive physiological effects when these cysteine derivatives are combined, a phenomenon difficult to explain when the compounds are structurally very similar. We present a simple theory to explain these results.