Multifunctional Tetrahydrocannabinol Derivatives as Potential Antioxidant Neuroprotectors: Computer-Aided Design and Analysis

Tetrahydrocannabinol (THC) and its derivatives exhibit a range of pharmacological activities, making them promising candidates for neuroprotective and antioxidant applications. This study employed computational approaches, including ADMET analysis, molecular docking and quantum chemical evaluations, to investigate the pharmacokinetic properties, antioxidant potential and receptor-binding interactions of 111 THC[Formula: see text] derivatives. The ADMET analysis identified 43 derivatives with favorable pharmacokinetic profiles, reduced toxicity and synthetic accessibility. Further refinement using exclusion ([Formula: see text] and elimination ([Formula: see text] factors narrowed the selection to 16 lead candidates, among which THC6, THC32and THC53 emerged as the most promising due to their optimal balance of pharmacokinetics, synthetic feasibility and biological activity. Quantum chemical analysis of the antioxidant potential, including ionization energy (IE) and electron affinity (EA), revealed that THC6, THC32 and THC53 exhibit superior electron- donating capacities, thereby reinforcing their ability to neutralize reactive oxygen species (ROS) and mitigate oxidative stress. Molecular docking studies revealed that these three derivatives exhibited the highest binding affinity for Beta-1 Secretase (BACE1), a key enzyme implicated in neurodegenerative pathways. Notably, THC6, THC32and THC53 displayed enhanced inhibitory potential compared to THC. Furthermore, docking analysis against cannabinoid receptors CB1 and CB2 demonstrated a reduced affinity for CB1, suggesting minimized psychoactive effects, while their selective interaction with CB2 indicates potential anti-inflammatory and immunomodulatory properties. Molecular dynamics (MDs) simulations further confirmed the structural stability and favorable binding profiles of the selected derivatives in complex with BACE1, supporting their dynamic compatibility with the target enzyme. These findings highlight THC6, THC32and THC53 as leading candidates for development as antioxidant neuroprotectors. Their ability to modulate oxidative stress, inhibit neurodegenerative enzymes and selectively target cannabinoid receptors underscores their therapeutic potential. Future studies, including in vitro and in vivo evaluations, will be crucial for further validating and optimizing these promising compounds for clinical applications.