Kaur Gagandeep, Mankoo Opinder Kaur, Kaur Amandeep, Mann Sukhmani, Priyadarshi Nitesh, Singh Prit Pal, Goyal Bhupesh, Singhal Nitin Kumar, Goyal Deepti
Department of Chemistry, Faculty of Basic and Applied Sciences, Sri Guru Granth Sahib World University, Fatehgarh Sahib, Punjab 140406, India.
National Agri-Food and Biomanufacturing Institute, S.A.S. Nagar, Punjab 140306, India.
ACS Chem Neurosci. 2025 Aug 6;16(15):3020-3037. doi: 10.1021/acschemneuro.5c00386. Epub 2025 Jul 25.
Alzheimer's disease (AD) is a neurological disorder characterized by a spectrum of symptoms such as memory loss and cognitive decline. AD is a multifaceted disease, and designing multipotent ligands is an effective strategy for AD treatment. In this regard, the pharmacophore moiety of clioquinol (CQ, metal chelator) was employed to design the multifunctional phenol-triazole derivatives (-). In particular, with an -I group on the phenyl ring displayed a noteworthy higher inhibition (inhibition efficiency = 90.5%, IC = 6.51 ± 0.01 μM) against Aβ aggregation as compared to 38.1% noted for CQ. Furthermore, significantly disassembled the preformed Aβ fibrils (Aβf, 92.5%), chelated Cu ions, and inhibited Cu-mediated Aβ aggregation. Compound ceases the production of reactive oxygen species (ROS) as it acts as an antioxidant due to the presence of a phenolic hydroxyl group. Compound has a sufficient safety-efficacy profile and alleviates the cytotoxicity by Aβ aggregates in PC-12 cells. For studying the modulation in the fibrillary architecture, hydrodynamic size, and structural transition of Aβ in the presence of , we resorted to transmission electron microscopy (TEM), dynamic light scattering (DLS), and circular dichroism (CD), respectively. The molecular dynamics (MD) simulations depicted a notable reduction in the conformational transformations in the Aβ monomer (Aβm) and Aβf on the incorporation of . Compound modulates Aβ fibrillation by maintaining a helix conformation and simultaneously reduces the sampling of β-sheet structures in Aβm, consistent with the CD results. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis depicted a favorable binding of to Aβm (-42.12 ± 7.14 kcal/mol) and Aβf (-74.42 ± 4.98 kcal/mol) with a significant contribution of van der Waals interactions to the binding free energy. The -induced deformation in Aβf chains noted in the conformational snapshots depicts its destabilization potential against Aβf. Finally, our results uncovered the potential of phenol-triazole derivatives as a promiscuous ligand for targeting various pathological conditions in AD. The key insights into the prevention of conformational transitions in Aβm and destabilization of Aβf by illuminated by experimental and computational studies are central to unraveling the molecular understanding of amyloid aggregation as well as designing future therapeutic candidates against multifaceted AD.
阿尔茨海默病（AD）是一种神经紊乱疾病，其特征为一系列症状，如记忆丧失和认知衰退。AD是一种多方面的疾病，设计多效配体是治疗AD的有效策略。在这方面，氯碘羟喹（CQ，金属螯合剂）的药效基团部分被用于设计多功能苯酚 - 三唑衍生物（-）。特别是，苯环上带有 -I 基团的化合物对Aβ聚集表现出显著更高的抑制作用（抑制效率 = 90.5%，IC = 6.51 ± 0.01 μM），相比之下，CQ的抑制率为38.1%。此外，该化合物能显著拆解预先形成的Aβ纤维（Aβf，92.5%），螯合铜离子，并抑制铜介导的Aβ聚集。化合物由于存在酚羟基而作为抗氧化剂，从而停止活性氧物种（ROS）的产生。化合物具有足够的安全 - 疗效特征，并能减轻PC - 12细胞中Aβ聚集体的细胞毒性。为了研究在该化合物存在下Aβ在纤维结构、流体动力学尺寸和结构转变方面的调节情况，我们分别采用了透射电子显微镜（TEM）、动态光散射（DLS）和圆二色性（CD）技术。分子动力学（MD）模拟表明，在加入该化合物后，Aβ单体（Aβm）和Aβf的构象转变显著减少。化合物通过维持螺旋构象来调节Aβ纤维化，同时减少Aβm中β - 折叠结构的采样，这与CD结果一致。分子力学泊松 - 玻尔兹曼表面积（MM - PBSA）分析表明该化合物与Aβm（-42.12 ± 7.14 kcal/mol）和Aβf（-74.42 ± 4.98 kcal/mol）具有良好的结合，范德华相互作用对结合自由能有显著贡献。在构象快照中观察到该化合物引起的Aβf链变形表明其对Aβf具有去稳定化潜力。最后，我们的结果揭示了苯酚 - 三唑衍生物作为针对AD中各种病理状况的混杂配体的潜力。通过实验和计算研究阐明的该化合物对Aβm构象转变的预防和Aβf去稳定化的关键见解，对于揭示淀粉样蛋白聚集的分子理解以及设计未来针对多方面AD的治疗候选物至关重要。
