Deep learning reveals why synthetic cannabinoids cause harmful effects.

Deep learning reveals why synthetic cannabinoids cause harmful effects.

New psychoactive substances and their significance

New psychoactive substances (NPS) were originally developed as possible painkillers but were discarded due to undesirable side effects. A new study from the University of Illinois Urbana-Champaign has shown that these substances could still have pharmaceutical value if researchers can better understand the causes of these side effects.

What are new psychoactive substances?

New psychoactive substances are synthetic compounds. One class of them mimics the effects of classic cannabinoids found in the cannabis plant. In contrast to classic cannabinoids, NPS activate different signaling pathways in the human brain. This can lead to more serious psychological effects.

The results of the study

The study found that NPS often activate a signaling pathway known as the “beta-arrestin pathway” instead of the “G-protein pathway” typically used by classic cannabinoids. This switching of signaling pathways can increase side effects.

The results were published in the specialist journaleLifepublished.

The largest class of NPS is often sold as street drugs Fubinaca, Chimica and Pinaca. In addition to the undesirable side effects, the formulas used to produce NPS vary, making them difficult to detect in standard drug tests.

Diwakar Shukla, Professor of Chemical and Biomolecular Engineering, University of Illinois Urbana-Champaign

How does research work?

In the lab, graduate student Soumajit Dutta used a new simulation method called Transition-Based Reweighting Method (TRAM) to estimate the thermodynamics and kinetics of slow molecular processes. This method allowed the team to observe the rare, slow molecular processes that occur when NPS is released from cannabinoid receptors.

In addition, the researchers used the Folding@Home platform, which enables millions of volunteers worldwide to provide computing power. This approach allowed the team to run many simulations in parallel and merge the results.

What does this mean for the future?

These methods allowed researchers to gain new physical insights into the interactions of NPS with receptors. These insights were previously difficult to access due to computational limitations. Research points the way to safer, cannabinoid-based medicines that could avoid harmful side effects.

By uncovering the NPS signals that are associated with more severe effects, researchers can now design new molecules that avoid these signaling pathways for medical applications. Shukla explained that their findings could guide more researchers to develop compounds that bind less tightly or come apart more easily, potentially reducing the drugs' harmful effects.

The National Institutes of Health and the National Science Foundation supported this research. Shukla is also affiliated with chemistry, bioengineering, the National Center for Supercomputing Applications, the Center for Digital Agriculture, and the Carl R. Woese Institute for Genomic Biology.

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