Masum Md Habib Ullah, Lokman Syed Mohammad, Parvin Rehana, Rahman Md Shahidur, Chowdhury Erfanul Haq, Chamonara Kazi, Chowdhury Salma, Mahdeen Ahmad Abdullah, Khatun Mst Mitu
Department of Genomics and Bioinformatics, Faculty of Biotechnology and Genetic Engineering, Chattogram Veterinary and Animal Sciences University, Khulshi, Bangladesh.
Asian University for Women (AUW), Chattogram, Bangladesh.
PLoS One. 2025 Jun 16;20(6):e0326219. doi: 10.1371/journal.pone.0326219. eCollection 2025.
Alzheimer's disease (AD), a progressive neurodegenerative disorder, is a major global health concern, affecting millions worldwide, with its prevalence expected to triple by 2050. Despite the widespread use of traditional drugs like cholinesterase inhibitors and NMDA receptor antagonists, their limited effectiveness requires innovative therapeutic approaches. This work used Computer-Aided Drug Design (CADD) to renovate AD therapies aimed at both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using fungal secondary metabolites. Subsequent pharmacokinetic profiles indicated that all metabolites had significant gastrointestinal absorption, blood-brain barrier permeability, and adherence to Lipinski's Rule of Five, suggesting favourable drug-like properties. Furthermore, these metabolites exhibited little toxicity, except for Lovastatin, which indicated possible carcinogenicity. Molecular docking revealed three main candidates-Fumitremorgin C, Hericenone J, and Lovastatin-with notable binding affinities for AChE and BuChE. Consequently, the Fumitremorgin C showed the highest affinity for AChE (-10.0 kcal/mol), but Hericenone J showed enhanced inhibition of BuChE (-9.2 kcal/mol), suggesting its potential use in advanced stages of AD. Molecular dynamics simulations spanning 100 ns validated the stability of enzyme-ligand complexes, with Hericenone J exhibiting the greatest stability, low RMSD, and strong hydrogen bond interactions. The RMSF analysis further demonstrated that Hericenone J preserved structural integrity, whereas ROG and SASA values validated its compactness and stability. As determined by binding energy calculations, Hericenone J had the most inhibitory potential, followed by Lovastatin. However, Hericenone J's constant adoption of low-energy conformations, as shown by the principal component and Gibbs free energy analyses, suggested robust and stable interactions with both cholinesterases. With its superior pharmacokinetic profiles, significant binding affinity, and high stability, Hericenone J is the most promising dual cholinesterase inhibitor. These results support the notion that Hericenone J might be an effective treatment for AD if subjected to more preclinical trials.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，是全球主要的健康问题，影响着全球数百万人，预计到2050年其患病率将增至三倍。尽管广泛使用了胆碱酯酶抑制剂和NMDA受体拮抗剂等传统药物，但其有限的疗效需要创新的治疗方法。这项研究利用计算机辅助药物设计（CADD），以真菌次生代谢产物为基础，对针对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）的AD治疗方法进行革新。随后的药代动力学研究表明，所有代谢产物都具有显著的胃肠道吸收、血脑屏障通透性，并符合Lipinski的五规则，显示出良好的类药物性质。此外，除了显示出可能致癌性的洛伐他汀外，这些代谢产物几乎没有毒性。分子对接显示了三种主要候选物——烟曲霉震颤素C、桑黄烯酮J和洛伐他汀——对AChE和BuChE具有显著的结合亲和力。因此，烟曲霉震颤素C对AChE显示出最高亲和力（-10.0千卡/摩尔），但桑黄烯酮J对BuChE的抑制作用增强（-9.2千卡/摩尔），表明其在AD晚期的潜在应用价值。长达100纳秒的分子动力学模拟验证了酶-配体复合物的稳定性，桑黄烯酮J表现出最大的稳定性、低均方根偏差（RMSD）和强烈的氢键相互作用。均方根波动（RMSF）分析进一步表明，桑黄烯酮J保持了结构完整性，而旋转半径（ROG）和溶剂可及表面积（SASA）值验证了其紧凑性和稳定性。通过结合能计算确定，桑黄烯酮J具有最大的抑制潜力，其次是洛伐他汀。然而，主成分分析和吉布斯自由能分析表明，桑黄烯酮J持续采用低能量构象，这表明它与两种胆碱酯酶之间存在强大而稳定的相互作用。凭借其优越的药代动力学特性、显著的结合亲和力和高稳定性，桑黄烯酮J是最有前途的双重胆碱酯酶抑制剂。这些结果支持了这样一种观点，即如果进行更多的临床前试验，桑黄烯酮J可能是一种有效的AD治疗药物。
