Alkaf Mohammed S, Said Musa A, Algamdi Noura A, Al-Kaff Nadia S
Mohammed Saleh Alkaf. College of Pharmacy, Clinical Pharmacy and Pharmaceutics Department, University of Aden, Yemen.
Department of Chemistry, Faculty of Science, Islamic University of Madinah, Madinah 42351, Saudi Arabia.
Curr Alzheimer Res. 2025 Aug 1. doi: 10.2174/0115672050386584250718130948.
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.
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.
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.
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.
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.
巧茶（Catha edulis Forssk.）是一种原产于非洲和亚洲的兴奋剂植物，含有卡西酮和去甲伪麻黄碱等影响中枢神经系统的精神活性化合物。本研究旨在调查与这些化合物相关的潜在神经毒理学风险，特别关注它们与阿尔茨海默病（AD）等神经退行性疾病的可能关系。主要目标是评估巧茶主要化合物的毒性，并研究它们与单胺氧化酶A（MAO - A）的分子相互作用，MAO - A是一种与AD病理学相关的酶。
使用Protox - 3服务器评估卡西酮、去甲伪麻黄碱、苯丙胺和AD药物多奈哌齐的毒理学特征，该服务器预测毒性类别、肝损伤可能性、致癌性、免疫毒性、致突变性和细胞毒性。进行分子对接研究以分析这些化合物与MAO - A（PDB ID：2Z5X）的结合相互作用。确定结合亲和力和关键相互作用残基。通过使用质心中心法计算埋藏体积（%VBur）来量化酶结合位点内配体的空间效应。
Protox - 3将去甲伪麻黄碱和苯丙胺归类为3类毒物（中度毒性），而卡西酮和多奈哌齐被归类为4类（较低毒性）。卡西酮还显示出中等程度的致癌可能性（0.64）。分子对接显示，巧茶化合物的平均结合亲和力为 - 5.81±0.27千卡/摩尔，低于苯丙胺（ - 6.10±0.27千卡/摩尔）和多奈哌齐（ - 7.80±0.38千卡/摩尔）。埋藏体积分析表明，巧茶化合物和苯丙胺在MAO - A结合位点中嵌入更深，这与更强的结合亲和力相关。
计算结果表明，巧茶化合物具有中等程度的神经毒性潜力，并以与AD病理学相关的方式与MAO - A相互作用。尽管结合亲和力低于苯丙胺和多奈哌齐，但它们表明可能存在对神经退行性变具有重要意义的分子水平相互作用。由%VBur量化的空间位阻似乎影响结合强度，突出了活性位点内分子契合的重要性。
本研究提供了食用巧茶与阿尔茨海默病风险增加之间潜在分子联系的证据。研究结果强调了进一步进行体内和流行病学研究的必要性，特别是在巧茶使用率高的地区，以评估其长期神经毒性作用。
