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G protein–coupled receptors, or GPCRs, are essential to signal transduction. The human genome encodes hundreds of GPCRs, which have been associated with diseases such as diabetes and cardiovascular abnormalities. Consequently, many GPCRs are drug targets.

Cannabinoid receptors are GPCRs expressed in our central and peripheral nervous systems as well as our immune system. Drugs targeting cannabinoid receptors 1 and 2, known as CB₁ and CB₂, initially showed great promise for the treatment of pain, obesity and inflammation but were removed from the market after they were shown to have adverse effects on patients. Researchers found that full agonists, which maximally activate the receptors when bound, were especially harmful. Therefore, many have turned their attention to the potential of partial agonists, which produce a smaller effect.

Delta-9-tetrahydrocannabinol, or Δ⁹-THC, is the euphoric psychoactive compound in marijuana. Researchers have found that it acts as a partial agonist of CB₁ and has positive effects in the treatment of Parkinson’s and other neurodegenerative diseases. However, the Food and Drug Administration still bans the sale of most THC products.

Soumajit Dutta, a Ph.D. candidate at the University of Illinois at Urbana–Champaign, uses molecular dynamic, or MD, simulations to study ligand interactions with CB₁ in hopes of understanding how full and partial agonists interact with the receptor. This could enable selective drug development targeting cannabinoid receptors. Combining his interests in computation and in mechanisms of allosteric modulation, Dutta and his team used computational analysis to understand why THC only partly activates CB₁.  They this research in the Journal of Biological Chemistry.

Using ligand and protein structures from the literature, Dutta performed unbiased molecular dynamics simulation with analysis by Markov state modeling to simulate the binding of THC to CB₁ in two poses, one that resembles agonist binding and one that resembles antagonist binding.

Full agonists of CB₁ “overstimulate the receptor, leading to negative side effects such as seizures or loss of motor function,” Dutta said, because a full agonist fills the large binding pocket, overexciting the receptor. On the other hand, THC is small and does not occupy much space in the binding pocket, allowing mobility within the pocket in order to activate the receptor without overstimulating.

An essential component in the activation of the CB₁ receptor is called the toggle switch, a tryptophan residue located in the binding pocket. Dutta made the novel finding that Δ⁹-THC had less interaction with the toggle switch residue within the active site pocket than a full agonist, which could explain why it works as only a partial agonist.

This research provided essential information about the mechanism of Δ⁹-THC binding to CB₁ and CB₂ so that drug developers can begin to design scaffolds to target CB₁ specifically. They hope such molecules will alleviate the negative side effects seen in early agonist cannabinoid receptor drugs. Meanwhile, Dutta plans to build on his research by looking at additional ligands in the database that also act as partial agonists on cannabinoid receptors.

The opioid and cannabinoid receptors are involved in pain sensation, mood, appetite and memory. Agonists are potent analgesics: endorphin (red) and tetrahydrocannabinol (green).