Quantitative Biology Lab, Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT, Deemed to be University), Vellore, Tamil Nadu, 632014, India; Department of Bioinformatics, Saveetha School of Engineering, SIMATS, Chennai, Tamil Nadu, India.
Quantitative Biology Lab, Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT, Deemed to be University), Vellore, Tamil Nadu, 632014, India.
Arch Biochem Biophys. 2022 Sep 30;727:109318. doi: 10.1016/j.abb.2022.109318. Epub 2022 Jun 9.
Deposition of misfolded protein aggregates in key areas of human brain is the quintessential trait of various pertinent neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). Genetic point mutations in Cu/Zn superoxide dismutase (SOD1) are found to be the most important contributing factor behind familial ALS. Especially, single nucleotide polymorphism (SNP) A4V is the most nocuous since it substantially decreases life expectancy of patients. Besides, the use of naturally occurring polyphenolic flavonoids is profoundly being advocated for palliating amyloidogenic behavior of proteopathic proteins. In the present analysis, through proficient computational tools, we have attempted to ascertain a pharmacodynamically promising flavonoid compound that effectively curbs the pathogenic behavior of A4V SOD1 mutant. Initial screening of flavonoids that exhibit potency against amyloids identified morin, myricetin and epigallocatechin gallate as promising leads. Further, with the help of feasible and yet adept protein-ligand interaction studies and stalwart molecular simulation analyses, we were able to observe that aforementioned flavonoids were able to considerably divert mutant A4V SOD1 from its distinct pathogenic behavior. Among which, morin showed the most curative potential against A4V SOD1. Therefore, morin holds a great therapeutic potential in contriving highly efficacious inhibitors in mitigating fatal and insuperable ALS.
错误折叠的蛋白质聚集体在人脑的关键区域沉积是各种相关神经退行性疾病（包括肌萎缩侧索硬化症（ALS））的典型特征。Cu/Zn 超氧化物歧化酶（SOD1）中的遗传点突变被认为是家族性 ALS 的最重要致病因素。特别是单核苷酸多态性（SNP）A4V 是最有害的，因为它大大降低了患者的预期寿命。此外，人们强烈提倡使用天然存在的多酚类黄酮来缓解蛋白构象病蛋白的淀粉样行为。在本分析中，我们通过熟练的计算工具，试图确定一种具有潜在药效的黄酮类化合物，该化合物能有效抑制 A4V SOD1 突变体的致病行为。对具有抗淀粉样特性的黄酮类化合物的初步筛选确定了杨梅素、杨梅素和表没食子儿茶素没食子酸酯是有前途的先导化合物。此外，通过可行且熟练的蛋白质-配体相互作用研究和坚定的分子模拟分析，我们能够观察到上述黄酮类化合物能够显著改变突变型 A4V SOD1 的独特致病行为。其中，杨梅素对 A4V SOD1 的治疗潜力最大。因此，杨梅素在设计高效抑制剂以减轻致命且不可避免的 ALS 方面具有很大的治疗潜力。
