Permana Afri, Akili Abd Wahid Rizaldi, Hardianto Ari, Latip Jalifah Binti, Sulaeman Allyn Pramudya, Herlina Tati
Department of Chemistry, Faculty of Mathematics and Natural Science, Universitas Padjadjaran, Sumedang, West Java, Indonesia.
Department of Chemical Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia (UKM), Selangor, Malaysia.
Adv Appl Bioinform Chem. 2025 Feb 5;17:179-201. doi: 10.2147/AABC.S495947. eCollection 2024.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options, necessitating the development of safer and more effective therapies. The potential of alkaloids derived from the genus as acetylcholinesterase (AChE) inhibitors is being investigated to enhance acetylcholine levels in the brain, which is crucial for the treatment of AD. The objective of this study is to identify Erythrina alkaloids with strong inhibitory capacity against AChE and favorable pharmacokinetic profiles.
A multi-step computational approach was employed, beginning with the virtual screening of 143 Erythrina alkaloid structures using molecular docking against the human AChE crystal structure. The binding affinities were compared with the known AChE inhibitor, galantamine. The top alkaloid, 8-oxoerymelanthine (), was subjected to further analysis through molecular dynamics simulations, with the objective of evaluating its stability and interactions. In silico ADMET predictions were conducted to assess the pharmacokinetic properties. The applicability of Lipinski's Rule of Five was applied to evaluate oral drug-likeness.
8-Oxoerymelanthine () exhibited the highest binding affinity and remarkable stability in molecular dynamics simulations. The toxicity predictions indicated a low risk of mutagenicity, hepatotoxicity, and cardiotoxicity. Pharmacokinetic assessments indicated good absorption, moderate blood-brain barrier penetration, and favorable metabolic and excretion profiles, supporting its potential as an orally active drug candidate.
8-Oxoerythmelanthine () exhibits strong potential as an AChE inhibitor with a favorable balance of efficacy, safety, and pharmacokinetic properties. These results warrant further investigation in preclinical and clinical studies to validate its therapeutic potential and safety for Alzheimer's disease treatment.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，治疗选择有限，因此需要开发更安全、更有效的疗法。人们正在研究刺桐属生物碱作为乙酰胆碱酯酶（AChE）抑制剂的潜力，以提高大脑中的乙酰胆碱水平，这对AD的治疗至关重要。本研究的目的是鉴定对AChE具有强抑制能力且具有良好药代动力学特征的刺桐生物碱。
采用多步骤计算方法，首先使用分子对接技术对143种刺桐生物碱结构与人类AChE晶体结构进行虚拟筛选。将结合亲和力与已知的AChE抑制剂加兰他敏进行比较。对顶级生物碱8-氧代刺桐文碱（）通过分子动力学模拟进行进一步分析，目的是评估其稳定性和相互作用。进行了计算机辅助的ADMET预测以评估药代动力学性质。应用Lipinski的五规则来评估口服药物相似性。
8-氧代刺桐文碱（）在分子动力学模拟中表现出最高的结合亲和力和显著的稳定性。毒性预测表明致突变性、肝毒性和心脏毒性风险较低。药代动力学评估表明其具有良好的吸收性、适度的血脑屏障穿透性以及良好的代谢和排泄特征，支持其作为口服活性药物候选物的潜力。
8-氧代刺桐文碱（）作为一种AChE抑制剂具有很强的潜力，在疗效、安全性和药代动力学性质方面具有良好的平衡。这些结果值得在临床前和临床研究中进一步研究，以验证其对阿尔茨海默病治疗的治疗潜力和安全性。
