Virtual Screening, Toxicity Evaluation and Pharmacokinetics of Erythrina Alkaloids as Acetylcholinesterase Inhibitor Candidates from Natural Products.

Q2 Biochemistry, Genetics and Molecular Biology
Advances and Applications in Bioinformatics and Chemistry Pub Date : 2025-02-05 eCollection Date: 2024-01-01 DOI:10.2147/AABC.S495947
Afri Permana, Abd Wahid Rizaldi Akili, Ari Hardianto, Jalifah Binti Latip, Allyn Pramudya Sulaeman, Tati Herlina
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Abstract

Purpose: 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 Erythrina 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.

Materials and methods: 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 (128), 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.

Results: 8-Oxoerymelanthine (128) 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.

Conclusion: 8-Oxoerythmelanthine (128) 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.

天然产物中赤藓生物碱作为乙酰胆碱酯酶抑制剂的虚拟筛选、毒性评价及药代动力学研究。
目的:阿尔茨海默病(AD)是一种进行性神经退行性疾病,治疗方案有限,需要开发更安全、更有效的治疗方法。从赤藓属提取的生物碱作为乙酰胆碱酯酶(AChE)抑制剂的潜力正在被研究,以提高大脑中乙酰胆碱的水平,这对治疗阿尔茨海默病至关重要。本研究的目的是鉴定对乙酰胆碱酯有较强抑制能力和良好的药代动力学特征的赤藓生物碱。材料和方法:采用多步骤计算方法,首先利用分子对接方法对143种赤藓生物碱结构进行虚拟筛选。与已知的乙酰胆碱酯酶抑制剂加兰他明的结合亲和力进行了比较。顶端的生物碱8-氧erymelanthine(128)通过分子动力学模拟进行了进一步分析,目的是评估其稳定性和相互作用。在计算机上进行ADMET预测以评估药代动力学性质。应用利平斯基五法则的适用性评价口服药物相似性。结果:8-氧erymelanthine(128)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。毒性预测显示其致突变性、肝毒性和心脏毒性的风险较低。药代动力学评估表明其具有良好的吸收、适度的血脑屏障穿透、良好的代谢和排泄特征,支持其作为口服活性候选药物的潜力。结论:8-氧赤melanthine(128)具有良好的疗效、安全性和药代动力学平衡,具有很强的AChE抑制剂潜力。这些结果值得在临床前和临床研究中进一步研究,以验证其治疗阿尔茨海默病的潜力和安全性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Advances and Applications in Bioinformatics and Chemistry
Advances and Applications in Bioinformatics and Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (miscellaneous)
CiteScore
6.50
自引率
0.00%
发文量
7
审稿时长
16 weeks
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