Department of Biochemistry, Faculty of Science and Technology, P.M.B 005, Karu, Nasarawa State, Nigeria.
Natural Products and Structural (Bio-Chem)-informatics Research Laboratory (NpsBC-Rl), Bingham University, Nasarawa, Nigeria.
Mol Divers. 2024 Jun;28(3):1305-1322. doi: 10.1007/s11030-023-10658-y. Epub 2023 Jun 20.
Neurodegenerative disorders (NDDs) are associated with increased activities of the brain acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and β-secretase enzyme (BACE1). Inhibition of these enzymes affords therapeutic option for managing NDDs such as Alzheimer's disease (AD) and Parkinson's disease (PD). Although, Gongronema latifolium Benth (GL) has been widely documented in ethnopharmacological and scientific reports for the management of NDDs, there is paucity of information on its underlying mechanism and neurotherapeutic constituents. Herein, 152 previously reported Gongronema latifolium derived-phytochemicals (GLDP) were screened against hAChE, hBChE and hBACE-1 using molecular docking, molecular dynamics (MD) simulations, free energy of binding calculations and cluster analysis. The result of the computational analysis identified silymarin, alpha-amyrin and teraxeron with the highest binding energies (-12.3, -11.2, -10.5 Kcal/mol) for hAChE, hBChE and hBACE-1 respectively as compared with those of the reference inhibitors (-12.3, -9.8 and - 9.4 for donepezil, propidium and aminoquinoline compound respectively). These best docked phytochemicals were found to be orientated in the hydrophobic gorge where they interacted with the choline-binding pocket in the A-site and P-site of the cholinesterase and subsites S1, S3, S3' and flip (67-75) residues of the pocket of the BACE-1. The best docked phytochemicals complexed with the target proteins were stable in a 100 ns molecular dynamic simulation. The interactions with the catalytic residues were preserved during the simulation as observed from the MMGBSA decomposition and cluster analyses. The presence of these phytocompounds most notably silymarin, which demonstrated dual high binding tendencies to both cholinesterases, were identified as potential neurotherapeutics subject to further investigation.
神经退行性疾病（NDDs）与大脑乙酰胆碱酯酶（AChE）、丁酰胆碱酯酶（BChE）和β-分泌酶（BACE1）的活性增加有关。抑制这些酶为治疗神经退行性疾病（如阿尔茨海默病（AD）和帕金森病（PD））提供了一种选择。尽管 Gongronema latifolium Benth（GL）在民族药理学和科学报告中被广泛记载用于治疗神经退行性疾病，但关于其潜在机制和神经治疗成分的信息却很少。在此，我们使用分子对接、分子动力学（MD）模拟、结合自由能计算和聚类分析筛选了 152 种先前报道的 Gongronema latifolium 衍生的植物化学物质（GLDP），以评估它们对 hAChE、hBChE 和 hBACE-1 的抑制作用。计算分析的结果表明，水飞蓟素、α-香树脂醇和特立枯灵与参考抑制剂（多奈哌齐、丙基和氨基喹啉化合物分别为-12.3、-9.8 和-9.4）相比，对 hAChE、hBChE 和 hBACE-1 的结合能最高（-12.3、-11.2 和-10.5 Kcal/mol）。这些最佳对接的植物化学物质被发现定向于疏水性峡谷中，在那里它们与胆碱酯酶的 A 位和 P 位以及口袋的亚位点 S1、S3、S3'和翻转（67-75）残基相互作用。在 100 ns 分子动力学模拟中，最佳对接的植物化学物质复合物与靶蛋白稳定。从 MMGBSA 分解和聚类分析中可以看出，在模拟过程中，与催化残基的相互作用得以保留。这些植物化合物的存在，特别是水飞蓟素，它表现出对两种胆碱酯酶的双重高结合倾向，被确定为具有潜在神经治疗作用的候选药物，有待进一步研究。
