Majumdar Featured in Nature Chemical Biology

Published on 29 November 2022

New research recently published in Nature Chemical Biology is shining further light on the structure, mechanisms of action and efficacy of lofentanil (LFT). Derived from fentanyl, LFT is one of the most potent lethal opioids, and is derived from fentanyl and mitragynine pseudoindoxyl (MP), a derivative from alkaloids found in the kratom plant.

The paper highlights the work of Susruta Majumdar, Ph.D., associate professor of medicinal chemistry and pharmacology at University of Health Sciences and Pharmacy in St. Louis, and his colleagues who examined the molecular differences between LFT and MP, and how they bind to MU opioid receptors.

Previously, Majumdar and his colleagues had shown that MP is a low efficacy-biased agonist and a minor metabolite formed when kratom is orally consumed.

The research team was led by Georgios Skiniotis, Ph.D., professor of molecular and cellular physiology and structural biology; Brian Kobilka, M.D., professor of molecular and cellular physiology at Stanford University and winner of the 2012 Nobel Prize in chemistry, and Ron Dror, associate professor of computer science in the Stanford Artificial Intelligence Lab.

“Using some pioneering cryoEM work from the Skiniotis and Kobilka labs, molecular simulation work from the Dror lab and functional characterization from our lab, we found that the kratom derivative, MP, binds very differently in the receptor,” Majumdar said. “MP possesses a binding pose in the receptor which leads to less efficacy. This lower efficacy possibly demonstrates enhanced safety with MP because it is less likely to cause respiratory depression and deaths compared to lofentanil at equianalgesic doses.”

Majumdar’s lab work featured the binding of the kratom-derived alkaloid and the fentanyl-derived alkaloid to get individual snapshots of each. By overlaying the snapshots, the research team was able to spot differences in how and where the alkaloids bind and provide a molecular rationale for the efficacy of each.

“Potent opioids like fentanyl have long been used as pain relievers across the U.S. and Canada, and while they are effective, they lead to overdoses and deaths,” Majumdar explained. “Our research is important because it helps the scientific community further understand how fentanyl functions at the molecular level, while also providing insights on kratom’s potential use as a viable analgesic for pain relief in the future.”

“On a larger scale, we also hope this work can provide additional insight from a chemical, pharmacological and societal perspective on the overall safety and effectiveness of both fentanyl and kratom,” Majumdar added.

View the full text of Majumdar’s paper.

Majumdar’s research is conducted through the Center for Clinical Pharmacology. Established in 2015, the Center for Clinical Pharmacology is a partnership between University of Health Sciences and Pharmacy in St. Louis and the Department of Anesthesiology at Washington University School of Medicine in St. Louis. The center continues to diversify with faculty investigators currently engaged in a variety of diverse research areas.

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