Computational Study on the Enzyme–Ligand Relationship between Cannabis Phytochemicals and Human Acetylcholinesterase: Implications in Alzheimer’s Disease

Cannabis has shown promise in treating various neurological disorders, including Alzheimer’s disease (AD). AD is a devastating neurodegenerative disorder that affects millions of people worldwide. Current treatments for AD are limited and are not very effective. This study investigated the enzyme–ligand relationship between nine active components of cannabis and human acetylcholinesterase (HuAChE) enzyme, which is significant in AD. Specifically, computational methods such as quantum mechanics, molecular docking, molecular dynamics, and free energy calculations were used to identify the cannabis phytochemicals with the highest HuAChE affinity and to understand the specific binding mechanisms involved. Our results showed that cannabichromene and cannabigerol were the cannabis phytochemicals with the highest affinity for HuAChE, with cannabichromene exhibiting the greatest binding energy. However, both substances showed lower affinity than that of the pharmaceutical drug donepezil. This study suggests that cannabichromene has a specific affinity for the peripheral anionic site (PAS) and acyl-binding pocket (ABP), while cannabigerol predominantly binds to PAS. Also, it was found that cannabichromene has a specific affinity for PAS and ABP, while cannabigerol predominantly binds to PAS. Our findings suggest that cannabichromene and cannabigerol are potential therapeutic agents, but further research is needed to validate their effectiveness. The specific binding mechanisms identified may also provide helpful information for the design of more effective cannabis-based drugs. Overall, this study provides valuable insights into the potential of cannabis-based drugs for treating neurological diseases.