Sofela Salimat O, Ibrahim Abdulwasiu, Ogbodo Uchechukwu C, Bodun Damilola S, Nwankwo Daniel O, Mafimisebi Mojirade, Abdulrasheed Buhari, Balogun Toheeb, Opeyemi Isaac
Department of Chemistry, University of Lagos, Lagos, Nigeria.
Department of Biochemistry and Molecular Biology, Usmanu Danfodiyo University, Sokoto, Nigeria.
In Silico Pharmacol. 2024 May 31;12(1):49. doi: 10.1007/s40203-024-00214-3. eCollection 2024.
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease that affects people aged 60 years and above. Yet, the discovery of potent therapeutic agents against this disease has no utmost progress and a number of drug candidates could not make it out of the clinical trials at varied stages. At the same time, the currently available anti-cholinesterase (AChE) and monoamine oxidase-B (MAO-B) for the treatment of AD can only improve the clinical symptoms while the recently approved immunotherapy agent "remains questionable. Thus, the need for novel therapeutic agents with the potential to treat the aetiology of the disease. Herein, this study sought to examine the potential of a number of bioactive compounds derived from as a promising agent against AChE and MAO-B. Using a computational approach via molecular docking 23 bioactive agents were screened against AChE and MAO-B, and the compounds with a binding score below that of the standard ligand were further subjected to drug-likeness and pharmacokinetic screening. Eight and thirteen of the studied agents optimally saturated the active pocket of the AChE and MAO-B respectively, forming principal interactions with a number of amino acids at the active pocket of the targets and among these compounds only rutin failed the drug-likeness test by violating four parameters while all showed moderate pharmacokinetics features. A number of derived bioactive compounds show excellent inhibitory potential against AChE and MAO-B, and moderate pharmacokinetic features when compared to the reference ligand (tacrine). These compounds are therefore proposed as novel AChE and MAO-B inhibitors for the treatment of AD and wet-lab analysis is necessary to affirm their potency.
阿尔茨海默病（AD）是影响60岁及以上人群的最常见神经退行性疾病。然而，针对这种疾病的有效治疗药物的研发进展甚微，许多候选药物在不同阶段的临床试验中未能成功。同时，目前用于治疗AD的抗胆碱酯酶（AChE）和单胺氧化酶-B（MAO-B）药物只能改善临床症状，而最近获批的免疫治疗药物也仍存在疑问。因此，需要有潜力治疗该疾病病因的新型治疗药物。在此，本研究旨在考察从[具体来源未给出]衍生的多种生物活性化合物作为抗AChE和MAO-B的有前景药物的潜力。通过分子对接的计算方法，对23种生物活性药物进行了针对AChE和MAO-B的筛选，结合分数低于标准配体的化合物进一步进行类药性和药代动力学筛选。所研究的药物中，分别有8种和13种最佳地饱和了AChE和MAO-B的活性口袋，与靶点活性口袋处的多个氨基酸形成主要相互作用，在这些化合物中，只有芦丁因违反四个参数而未通过类药性测试，而所有化合物均表现出中等的药代动力学特征。与参考配体（他克林）相比，许多衍生的生物活性化合物对AChE和MAO-B显示出优异的抑制潜力，以及中等的药代动力学特征。因此，这些化合物被提议作为治疗AD的新型AChE和MAO-B抑制剂，需要进行湿实验室分析来确认它们的效力。
