New research from the University of Illinois Urbana-Champaign indicates that understanding the side effects of new psychoactive substances (NPS) could lead to the development of safer cannabinoid drugs. These substances, initially intended as pain relievers, have been sidelined due to adverse reactions. The study employs advanced deep learning and extensive computer simulations to explore how structural variations in synthetic cannabinoids affect their interaction with human brain receptors.
Professor Diwakar Shukla, who leads the research team, explained that NPS are often marketed as street drugs, including names such as Fubinaca, Chimica, and Pinaca. “In addition to the adverse side effects, the formulas used to produce NPS vary, making them challenging to detect in standard drug screenings,” Shukla stated.
The study highlights a significant finding: NPS activate distinct signaling pathways in the brain. Unlike classical cannabinoids, NPS tend to trigger the “beta arrestin pathway” instead of the “G protein pathway.” This shift can result in more severe psychological effects, complicating their use in medical settings. The findings are documented in the journal eLife.
Shukla noted the complexity of studying these substances. “New psychoactive substances bind very strongly to cannabinoid receptors in the brain and are slow to unbind, making them difficult to observe and simulate in standard laboratory or computer experiments,” he said. The research team utilized a novel simulation technique called the Transition-Based Reweighting Method (TRAM) to estimate the thermodynamics and kinetics of these slow molecular processes.
In the laboratory, graduate student Soumajit Dutta applied TRAM to effectively analyze the unbinding of NPS from cannabinoid receptors. This method allowed the researchers to sample rare events that would typically require substantial computing resources. The team also leveraged the Folding@Home platform, which enables global volunteers to contribute computing power, facilitating numerous simultaneous simulations. The combined approach allowed for the exploration of long or infrequent events that would be nearly impossible to study with limited computational capacity.
These innovative techniques enabled the researchers to gain insights into how NPS interact with receptors, leading toward the design of cannabinoid-based drugs that minimize harmful side effects. By illuminating the signaling pathways associated with more adverse effects, the study provides a pathway for developing new molecules that do not trigger these pathways.
Shukla emphasized the potential impact of these findings, suggesting that they could inspire researchers to create compounds that either bind less tightly or unbind more readily, thereby reducing the risk of adverse effects.
The research received funding from the National Institutes of Health under award number R35GM-142745 and the National Science Foundation. Shukla is affiliated with multiple departments, including chemistry and bioengineering, as well as several research centers within the university.
As the scientific community seeks safer alternatives in cannabinoid therapies, this study marks a significant step forward in understanding the nuances of synthetic substances and their interactions within the human body.
