Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, 643001, TN, India.
Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, 643001, TN, India.
Curr Comput Aided Drug Des. 2024;20(6):998-1012. doi: 10.2174/0115734099270256231018072007.
Alzheimer's disease (AD) is one of the most concerned neurodegenerative disorders across the world characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs), leading to cognitive decline and memory loss. Targeting key pathways involved in AD like Aβ and NFT pathways, are crucial for the development of effective therapeutic strategies. In this study, we aimed to identify and establish promising dual inhibitors targeting BACE1 and GSK-3β, two proteins implicated in Aβ and NFT formation respectively.
We have used molecular docking, ADME property analysis, and MMGBSA calculations for the identification of hit molecules and further evaluation of binding affinity, drug-like properties, and stability against BACE1 and GSK-3β.
Our results demonstrated strong binding affinities of ZINC000034853956 towards the active sites of both proteins, with favorable interactions involving key residues crucial for inhibitory activity. Additionally, ZINC000034853956 exhibited favorable drug-like properties. MD simulations revealed the stable binding of ZINC000034853956 to both BACE1 and GSK-3β over a 50 ns period, with consistent ligand-protein interactions, such as hydrogen bonding and hydrophobic contacts. These findings highlight the potential of ZINC000034853956 as a promising candidate for AD treatment, acting as a dual inhibitor targeting both BACE1 and GSK-3β. Overall, our study provides valuable insights into the potential of ZINC000034853956 as a dual inhibitor for AD. The strong binding affinity, favorable drug-like properties, and stability observed in MD simulations support its suitability for further optimization and preclinical studies.
Further investigations are warranted to elucidate the precise molecular mechanisms and therapeutic benefits of ZINC000034853956. Our findings offer hope for the development of novel therapeutic interventions targeting crucial pathways involved in AD neurodegeneration.
阿尔茨海默病（AD）是全球最受关注的神经退行性疾病之一，其特征是淀粉样β（Aβ）斑块和神经原纤维缠结（NFTs），导致认知能力下降和记忆力丧失。针对 AD 相关的关键途径，如 Aβ 和 NFT 途径，是开发有效治疗策略的关键。在这项研究中，我们旨在鉴定和建立有前途的针对 BACE1 和 GSK-3β 的双重抑制剂，这两种蛋白分别与 Aβ 和 NFT 的形成有关。
我们使用分子对接、ADME 性质分析和 MMGBSA 计算来鉴定命中分子，并进一步评估它们与 BACE1 和 GSK-3β 的结合亲和力、类药性和稳定性。
我们的结果表明，ZINC000034853956 与两种蛋白质的活性部位具有很强的结合亲和力，与关键残基的有利相互作用对抑制活性至关重要。此外，ZINC000034853956 表现出良好的类药性。MD 模拟显示，ZINC000034853956 在 50 ns 的时间内稳定地与 BACE1 和 GSK-3β 结合，配体-蛋白相互作用一致，如氢键和疏水接触。这些发现强调了 ZINC000034853956 作为 AD 治疗的有前途的候选物的潜力，它作为一种针对 BACE1 和 GSK-3β 的双重抑制剂。总的来说，我们的研究为 ZINC000034853956 作为 AD 的双重抑制剂提供了有价值的见解。在 MD 模拟中观察到的强结合亲和力、有利的类药性和稳定性支持了它进一步优化和临床前研究的适用性。
需要进一步的研究来阐明 ZINC000034853956 的精确分子机制和治疗益处。我们的发现为针对 AD 神经退行性变中关键途径的新型治疗干预措施的发展提供了希望。
