For the last several years, we have been collaborating with the lab of Dr. Stephen J. Lewis of Case Western Reserve University to develop cysteine derivatives as therapeutics for opioid overdose. Lewis and coworkers have shown that cysteine derivatives can reverse the effects of opioids in rats, while my group has worked on unconvering the mechanism of action. We have focused on the interaction of these compounds, e.g. D-cysteine ethyl ester, with beta-arrestins, proteins that regulate the internalization and recycling of GPCRs like opioid receptors. We have combined conventional molecular dynamics simulations with alchemical ligand binding free energy calculations.

Preprints in this area:

  • Emily Weed-Nichols, James M. Seckler, Paulina M. Getsy, Stephen J. Lewis, Alan Grossfield. A simple theory to explain super-additivity of highly similar drug combinations, bioRxiv 2025.10.27.684841; doi

Publications in this area:

  • Getsy PM, May WJ, Henderson F Jr, Seckler JM, Grossfield A, Baby SM, Lewis SJ., Nitrosyl factors play a vital role in the ventilatory depressant effects of fentanyl in freely moving guinea pigs, Biomed Pharmacother. 2025 Feb;183:117847. doi: 10.1016/j.biopha.2025.117847.
  • Getsy PM, May WJ, Henderson F Jr, Seckler JM, Grossfield A, Baby SM, Lewis SJ., S-Nitroso-L-Cysteine Stereoselectively Blunts the Deleterious Effects of Fentanyl on Breathing While Augmenting Antinociception in Freely-Moving Rats, Front Pharmacol. 2022 May 26;13:892307. doi: 10.3389/fphar.2022.892307.
  • Getsy PM, Young AP, Grossfield A, Seckler JM, Wilson CG, Gaston B, Bates JN, Lewis SJ., D-cysteine ethyl ester and D-cystine dimethyl ester reverse the deleterious effects of morphine on arterial blood-gas chemistry and Alveolar-arterial gradient in anesthetized rats, Respir Physiol Neurobiol. 2022 Aug;302:103912. doi: 10.1016/j.resp.2022.103912
  • Seckler JM, Robinson EN, Lewis SJ, Grossfield A., Surveying nonvisual arrestins reveals allosteric interactions between functional sites, Proteins. 2023 Jan;91(1):99-107. doi: 10.1002/prot.26413
  • Benjamin Gaston, Santhosh M Baby , Walter J May, Alex P Young, Alan Grossfield, James N Bates, James M Seckler , Christopher G Wilson, Stephen J Lewis, “D-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception“, Scientific Reports, 2021, 11;11(1):10038, pdf