Unveiling the Potential Role of Cathinone and Cathine Compounds in Alzheimer's Disease: Predictive Insights.

Introduction: Khat (Catha edulis Forssk.), a stimulant plant native to Africa and Asia, contains psychoactive compounds such as cathinone and cathine that affect the central nervous system. This study aims to investigate the potential neurotoxicological risks associated with these compounds, particularly focusing on their possible relationship with neurodegenerative disorders like Alzheimer's disease (AD). The primary objective was to evaluate the toxicity of khat's main compounds and examine their molecular interactions with Monoamine Oxidase A (MAO-A), an enzyme implicated in the pathology of AD.

Methods: The toxicological profiles of cathinone, cathine, amphetamine, and the AD medication Donepezil were assessed using the Protox-3 server, which predicted toxicity class, potential for liver damage, carcinogenicity, immunotoxicity, mutagenicity, and cytotoxicity. Molecular docking studies were conducted to analyse the binding interactions of these compounds with MAO-A (PDB ID: 2Z5X). Binding affinities and key interacting residues were identified. The steric effects of the ligands within the enzyme's binding site were quantified by calculating the buried volume (%VBur) using the centroid of centres method.

Results: Protox-3 classified cathine and amphetamine as Class 3 toxicants (moderate toxicity), while cathinone and Donepezil were assigned to Class 4 (lower toxicity). Cathinone also demonstrated a moderate probability (0.64) of carcinogenicity. Molecular docking revealed that khat compounds had an average binding affinity of -5.81 ± 0.27 kcal/mol, which was lower than that of amphetamine (-6.10 ± 0.27 kcal/mol) and Donepezil (-7.80 ± 0.38 kcal/mol). Buried volume analysis indicated that khat compounds and amphetamine were more deeply embedded in the MAO-A binding site, correlating with stronger binding affinity.

Discussion: The computational results suggest that khat compounds exhibit moderate neurotoxic potential and interact with MAO-A in a manner that could be relevant to AD pathology. Although the binding affinities are lower than those of Amphetamine and Donepezil, they point to possible molecular-level interactions significant for neurodegeneration. Steric hindrance, as quantified by %VBur, appeared to influence binding strength, highlighting the importance of molecular fit within the active site.

Conclusion: This study presents evidence of a potential molecular link between khat consumption and an increased risk of Alzheimer's disease. The findings underscore the necessity for further in vivo and epidemiological research, particularly in regions with high rates of khat use, to assess its long-term neurotoxic effects.