Neurobiology Laboratory, Atta ur Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad 44000, Pakistan.
Center for Computational Chemistry, School of Chemistry, University of Bristol, Bristol BS8 1TH, UK.
Molecules. 2022 Oct 25;27(21):7241. doi: 10.3390/molecules27217241.
Alzheimer's disease (AD) has been associated with the hallmark features of cholinergic dysfunction, amyloid beta (Aβ) aggregation and impaired synaptic transmission, which makes the associated proteins, such as β-site amyloid precursor protein cleaving enzyme 1 (BACE I), acetylcholine esterase (AChE) and synapsin I, II and III, major targets for therapeutic intervention. The present study investigated the therapeutic potential of three major phytochemicals of ursolic acid (UA), rosmarinic acid (RA) and carnosic acid (CA), based on their binding affinity with AD-associated proteins. Detailed docking studies were conducted using AutoDock vina followed by molecular dynamic (MD) simulations using Amber 20. The docking analysis of the selected molecules showed the binding energies of their interaction with the target proteins, while MD simulations comprising root mean square deviation (RMSD), root mean square fluctuation (RMSF) and molecular mechanics/generalized born surface area (MM/GBSA) binding free energy calculations were carried out to check the stability of bound complexes. The drug likeness and the pharmacokinetic properties of the selected molecules were also checked through the Lipinski filter and ADMETSAR analysis. All these bioactive compounds demonstrated strong binding affinity with AChE, BACE1 and synapsin I, II and III. The results showed UA and RA to be potential inhibitors of AChE and BACE1, exhibiting binding energies comparable to those of donepezil, used as a positive control. The drug likeness and pharmacokinetic properties of these compounds also demonstrated drug-like characteristics, indicating the need for further in vitro and in vivo investigations to ascertain their therapeutic potential for AD.
阿尔茨海默病（AD）与胆碱能功能障碍、β-淀粉样蛋白（Aβ）聚集和突触传递受损的标志性特征有关，这使得相关蛋白，如β-位点淀粉样前体蛋白裂解酶 1（BACE1）、乙酰胆碱酯酶（AChE）和突触素 I、II 和 III，成为治疗干预的主要靶点。本研究基于与 AD 相关蛋白的结合亲和力，研究了熊果酸（UA）、迷迭香酸（RA）和卡诺酸（CA）这三种主要植物化学物质的治疗潜力。使用 AutoDock vina 进行详细的对接研究，然后使用 Amber 20 进行分子动力学（MD）模拟。所选分子的对接分析显示了它们与靶蛋白相互作用的结合能，而包括均方根偏差（RMSD）、均方根波动（RMSF）和分子力学/广义 Born 表面积（MM/GBSA）结合自由能计算在内的 MD 模拟用于检查结合复合物的稳定性。还通过 Lipinski 过滤器和 ADMET SAR 分析检查了所选分子的药物相似性和药代动力学特性。所有这些生物活性化合物都与 AChE、BACE1 和突触素 I、II 和 III 表现出很强的结合亲和力。结果表明，UA 和 RA 可能是 AChE 和 BACE1 的抑制剂，其结合能与用作阳性对照的多奈哌齐相当。这些化合物的药物相似性和药代动力学特性也表现出类药性特征，表明需要进一步进行体外和体内研究，以确定它们对 AD 的治疗潜力。
