Dutta Ankumoni, Bhattacharya Pallab, Chutia Pavitra, Borah Anupom
Department of Life Science and Bioinformatics, Cellular and Molecular Neurobiology Laboratory, Assam University, Silchar, Assam 788011 India.
Department of Zoology, Pandit Deendayal Upadhyaya Adarsha Mahavidyalaya (PDUAM), Behali, Biswanath, Assam 784184 India.
In Silico Pharmacol. 2024 Jun 3;12(1):50. doi: 10.1007/s40203-024-00226-z. eCollection 2024.
Alzheimer's disease (AD) is the most occurring neurodegenerative disorder that destroys learning, memory, and thinking skills. Although the pathophysiology of the disease is least understood, the post-mortem brain of AD patients as well as animal models revealed the part of down regulated Wnt signalling in progression of the disease. The deficit in the Wnt signalling leads to the accumulation of amyloid beta peptides, phosphorylation of tau proteins, and synaptic dysfunctions, which are regarded as the major pathological features of AD. As the available drugs for AD are only able to mitigate the symptoms and are also associated with several side effects, the therapeutic potential of the bioactive compounds is being explored for their efficacies in managing the major pathologies. Consequently, a few bioactive compounds fundamentally isolated from species are established as promising neuroprotective agents in AD, however; their potential to regulate the Wnt signalling pathway is yet to be discovered. Considering the neuroprotective properties, in the present study efficiency of six small bioactive compounds viz., amentoflavone, isovitexin, orientin, apigenin, kaempferol, and garcinol have been investigated in modulating the receptor proteins (LRP6, DKK1, WIF1 and GSK3β) of the Wnt signalling pathway by molecular docking technique. While all the bioactive compounds could efficiently interact with the target proteins, amentoflavone, orientin, and isovitexin interact with all the target proteins viz., LRP6, DKK1, WIF1, and GSK3β with higher free energy of binding, more number of interactions, and similar mode of binding in comparison to their known or reported modulators. Thus, the present study set forth the investigated small bioactive molecules as potential drug candidates in AD therapeutics.
阿尔茨海默病（AD）是最常见的神经退行性疾病，会破坏学习、记忆和思维能力。尽管对该疾病的病理生理学了解最少，但AD患者的尸检大脑以及动物模型显示，在疾病进展过程中Wnt信号通路部分下调。Wnt信号通路的缺陷会导致淀粉样β肽的积累、tau蛋白的磷酸化以及突触功能障碍，这些被认为是AD的主要病理特征。由于现有的AD药物只能缓解症状，且还伴有多种副作用，因此正在探索生物活性化合物在管理主要病理方面的治疗潜力。因此，一些从物种中基本分离出来的生物活性化合物被确立为AD中有前景的神经保护剂，然而；它们调节Wnt信号通路的潜力尚未被发现。考虑到神经保护特性，在本研究中，通过分子对接技术研究了六种小生物活性化合物，即穗花杉双黄酮、异荭草素、东方蓼黄素、芹菜素、山奈酚和藤黄酸在调节Wnt信号通路受体蛋白（LRP6、DKK1、WIF1和GSK3β）方面的效率。虽然所有生物活性化合物都能与靶蛋白有效相互作用，但穗花杉双黄酮、东方蓼黄素和异荭草素与所有靶蛋白，即LRP6、DKK1、WIF1和GSK3β相互作用，与它们已知或报道的调节剂相比，具有更高的结合自由能、更多的相互作用数量和相似的结合模式。因此，本研究提出所研究的小生物活性分子作为AD治疗中的潜在候选药物。
