Abstract：
Alzheimer\'s disease (AD) is a chronic neurodegenerative condition characterized by progressive cognitive impairment. While the formation of β-amyloid plaques and neurofibrillary tangles are the hallmarks features of AD, the downstream consequence of these byproducts is the disruption of the cholinergic and glutamatergic neural systems. Growing evidence for the existence of interplay between AChE and NMDARs has opened up new venues for the discovery of novel ligands endowed with anticholinesterase and NMDAR-blocking activity. Plants belonging to the stachys genus have been extensively explored for having a broad range of therapeutic applications and have been used traditionally for millennia, to treat various CNS-related disorders, which makes them the ideal source of novel therapeutics. The present study was designed to identify natural dual-target inhibitors for AChE and NMDAR deriving from stachys genus for their potential use in AD. Using molecular docking, drug-likeness-profiling, MD simulation and MMGBSA calculations, an in-house database of biomolecules pertaining to the stachys genus was shortlisted based on their binding affinity, overall stability and critical ADMET parameters. Pre- and post-MD analysis revealed that Isoorientin effectively binds to AChE and NMDAR with various vital interactions, exhibits a stable behavior with minor fluctuations relative to two clinical drugs used as positive control, and displays strong and consistent interactions that lasted for the majority of the simulation. Findings from this study have elucidated the rationale behind the traditional use of Stachys plants for the treatment of AD and could provide new impetus for the development of novel dual-target therapeutics for AD treatment.Communicated by Ramaswamy H. Sarma.
摘要：
阿尔茨海默病(AD)是一种以进行性认知损害为特征的慢性神经退行性疾病。而β-淀粉样斑块的形成和神经原纤维缠结是AD的标志特征,这些副产物的下游后果是胆碱能和谷氨酸能神经系统的破坏。越来越多的证据表明AChE和NMDAR之间存在相互作用，为发现具有抗胆碱酯酶和NMDAR阻断活性的新型配体开辟了新的场所。属于stachys属的植物已被广泛探索，具有广泛的治疗应用，并已在传统上使用了数千年，治疗各种中枢神经系统相关疾病，这使得它们成为新疗法的理想来源。本研究旨在鉴定源自stachys属的AChE和NMDAR的天然双靶标抑制剂在AD中的潜在用途。利用分子对接，药物相似性分析，MD模拟和MMGBSA计算，根据其结合亲和力，入围了与stachys属有关的生物分子的内部数据库，整体稳定性和关键ADMET参数。前和后MD分析显示，Isoorientin与AChE和NMDAR有效结合，具有各种重要的相互作用，相对于用作阳性对照的两种临床药物，表现出稳定的行为，波动较小，并显示出持续大部分模拟的强大且一致的交互。这项研究的结果阐明了传统使用Stachys植物治疗AD的基本原理，并可能为开发用于AD治疗的新型双靶标疗法提供新的动力。由RamaswamyH.Sarma沟通。
