Upadhayay Priyank, Sinha Saurabh K, Kumar Neeraj, Singh Shashi Kant, Jain Preet, Panchawat Sunita, Rai Nitish
Department of Biotechnology, Mohanlal Sukhadia University, Udaipur, India.
Department of Pharmaceutical Sciences, Mohanlal Sukhadia University, Udaipur, Rajasthan, India.
J Aging Res. 2025 Mar 25;2025:7062203. doi: 10.1155/jare/7062203. eCollection 2025.
Alzheimer's disease (AD) is a commonly occurring neurodegenerative disease in elderly and it is a leading cause of dementia worldwide. Hydroxychavicol (HC), a major phenolic component of has prominent anti-inflammatory and antioxidant properties, and studies have found its role in cognition improvement. Here is a systematic approach to deciphering the potential protein targets of HC in AD through network pharmacology and validation from molecular docking and dynamics simulation study. First, the druglikeliness of HC was predicted using the SwissADME analysis, which showed significant druglikeliness. A total of 88 possible target genes between HC and AD were obtained from the Swiss Target Prediction, HIT Version 2, DisGeNET, and GeneCards database. The pathway analysis was carried out using the STRING database which showed several genes including COMT, HSP90AA1, and GAPDH as the top hub genes on the basis of degree. GO and KEGG analyses demonstrated that the core targets were mainly involved in cAMP, PI3K/AkT, HIF1, Rap1, and Calcium signaling pathways. The molecular docking of HC with top hub genes resulted in the highest binding of HC with COMT (-8.9 kcal/mol), GAPDH (-6.7 kcal/mol), and HSP90AA1 (-6.5 kcal/mol) that showed stable binding in the molecular dynamics simulation study. COMT regulates the dopamine levels in the prefrontal cortex and impairment of the COMT is associated with the rapid progression of AD. HSP90, a ubiquitous molecular chaperone, is involved in regulating tau metabolism and Aβ processing and found to be downregulated in AD. GAPDH has been reported as the disease-susceptible gene in AD and its interaction with amyloid precursor protein and NFTs has also been reported. These findings suggest that HC is a promising therapeutic candidate, targeting multiple AD-related pathways, warranting further investigation into its molecular mechanisms and potential for clinical application.
阿尔茨海默病（AD）是老年人中常见的神经退行性疾病，是全球痴呆症的主要病因。羟基查耳酮（HC）是[植物名称未给出]的主要酚类成分，具有显著的抗炎和抗氧化特性，研究发现其在改善认知方面发挥作用。本文采用网络药理学方法，并通过分子对接和动力学模拟研究进行验证，系统地解析了HC在AD中的潜在蛋白质靶点。首先，使用SwissADME分析预测了HC的类药性质，结果显示其具有显著的类药性质。通过Swiss Target Prediction、HIT Version 2、DisGeNET和GeneCards数据库共获得了88个HC与AD之间可能的靶基因。使用STRING数据库进行通路分析，结果显示包括儿茶酚-O-甲基转移酶（COMT）、热休克蛋白90α（HSP90AA1）和甘油醛-3-磷酸脱氢酶（GAPDH）等多个基因是基于度的顶级枢纽基因。基因本体（GO）和京都基因与基因组百科全书（KEGG）分析表明，核心靶点主要参与环磷酸腺苷（cAMP）、磷脂酰肌醇-3激酶/蛋白激酶B（PI3K/AkT）、缺氧诱导因子1（HIF1）、Rap1和钙信号通路。HC与顶级枢纽基因的分子对接结果显示，HC与COMT（-8.9千卡/摩尔）、GAPDH（-6.7千卡/摩尔）和HSP90AA1（-6.5千卡/摩尔）结合力最高，在分子动力学模拟研究中显示出稳定的结合。COMT调节前额叶皮质中的多巴胺水平，COMT功能受损与AD的快速进展有关。HSP90是一种普遍存在的分子伴侣，参与调节tau蛋白代谢和淀粉样前体蛋白（Aβ）的加工，且在AD中被发现表达下调。GAPDH已被报道为AD中的疾病易感基因，并且也有报道其与淀粉样前体蛋白和神经纤维缠结的相互作用。这些发现表明，HC是一种有前景的治疗候选物，靶向多个与AD相关的通路，值得进一步研究其分子机制和临床应用潜力。
