Researchers have discovered how tetrahydrocannabinol (THC), the main psychoactive compound in Cannabis sativa, along with 10 of its analogues, binds to a brain receptor that influences sleep, appetite and mood. A researcher says that understanding THC will enable the pharmaceutical industry to design medicines that replicate the effects of THC but without side-effects.
THC is the compound in cannabis causing its unique psychoactive effects, influencing sleep, appetite and mood. The pharmaceutical industry is keenly interested in understanding how THC functions and exploring whether it can be modified to achieve more potent or targeted effects – without side-effects.
Researchers developed this understanding in a new study determining the interactions between THC and 10 structurally similar THC analogues and the cannabinoid 1 (CB1) receptor in the brain to which THC binds. This revealed the factors determining how potent THC and its analogues are, how effective they are and the mechanisms by which they work.
This provides pharmaceutical companies valuable insight into designing THC-like medicines that achieve the desired effects more precisely.
The research has been published in Nature Communications.
“THC is the focal point, and understanding its structure is key to designing better medicines with similar effects. This study highlights how the structure of THC and its analogues influence their effects,” explains a researcher behind the study, David Gloriam, Professor, Department of Drug Design and Pharmacology, University of Copenhagen, Denmark.
The research was carried out in collaboration with researchers from the University of Nottingham, United Kingdom, Aarhus University, Denmark and Northeastern University, Boston, United States.
Computer simulation of binding affinity
Researchers can compare molecular structures and their effects in various ways. One experimental method involves incrementally changing the molecular structure, such as adding a moiety, and then observing how this affects cells or laboratory animals.
There are also more rapid ways to achieve this. David Gloriam and colleagues use very advanced computer models to simulate minor changes in the structure of THC analogues and observe how they affect binding to the CB1 receptor.
Researchers can use structural models that display each atom in the ligands and the receptor, similar to observing how a key fits into a lock.
However, David Gloriam and colleagues advanced this approach by using dynamic models, enabling them to study both ligands and receptors as they dynamically interact and change conformation during molecular simulations.
“This approach deepens the insight into the interactions between molecules and their receptors. We simulated the binding process for 1,000 nanoseconds, which is similar to observing and capturing the interaction between molecules and their receptors through a high-speed camera. Although this method requires extensive simulation, it also generates myriad data for analysis,” he says.
Facilitating the design of medicines
The researchers carried out simulations to correlate the structures of THC and its 10 analogues to parameters such as potency, effectiveness and off-rate – the rate at which they release their bonds. All three are crucial in determining the efficacy of an active pharmaceutical ingredient.
David Gloriam explains that based on molecular insight from THC and its 10 analogues, developers can design medicines with precise structures to achieve the desired potency, efficacy and off-rate.
The researchers can identify specific types of molecular moiety and how they affect the bond between molecules and receptors, determining how these change the medicine’s binding affinity and efficacy.
“Traditional methods can determine the interaction between molecules and receptors but do not provide information about the dynamics. Our approach enables us to observe how the interaction is transient, with the bond constantly shifting between being present and absent,” notes David Gloriam.
Most accurate assessment of THC analogues
In addition to simulating the interactions between THC and its 10 analogues with the CB1 receptor, the researchers achieved the most precise determination so far of the molecular structure of the THC analogue HU210 when it binds to CB1.
The researchers accomplished this by using cryogenic electron microscopy (cryo-EM), which freezes molecules to minus 200°C and maps their structure with an electron microscope. Cryo-EM enables researchers to determine the precise positions of all atoms within a molecule.
According to David Gloriam, the detailed structure of HU210 is especially interesting because it is frequently used in research.
These new discoveries will enable researchers and pharmaceutical companies to more easily understand the interactions between THC or a THC ligand and the CB1 receptor and how to modulate these interactions to change the effects.
“Building a house requires an architectural blueprint. The same principle applies in designing medicine: a blueprint is required. Structural biology provides this and tells how to design a medicine to achieve a specific effect. Our study contributes to creating these blueprints,” concludes David Gloriam.
