Computer-Aided Design and Analysis of Multifunctional Tetrahydrocannabinol Derivatives Targeting Acetylcholinesterase as Potential Antioxidant Neuroprotectors for Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, oxidative stress, and cholinergic dysfunction. Current therapies offer limited efficacy, highlighting the need for new neuroprotective agents. Tetrahydrocannabinol (THC), the main psychoactive component of cannabis, exhibits antioxidant and neuroprotective properties, but its clinical use is restricted due to psychoactivity. To overcome this, a series of structurally modified THC derivatives were designed using a computer-aided drug design approach aimed at enhancing drug-likeness and reducing adverse effects. Derivatives were evaluated for pharmacokinetic properties, synthetic accessibility, and antioxidant potential. Molecular docking simulations were used to assess binding interactions with acetylcholinesterase (AChE), a key enzyme involved in AD pathology. Among all derivatives, THC3 and THC53 emerged as the most promising, demonstrating strong binding to AChE and favorable physicochemical profiles. These findings support their potential as multifunctional agents for AD treatment, combining acetylcholinesterase inhibition with antioxidant neuroprotection. Together, these results highlight the potential of rational drug design in developing new therapies for neurodegenerative diseases.