Department of Molecular and Cell Biology, Faculty of Basic Science, University of Mazandaran, Babolsar, Iran.
Department of Molecular and Cell Biology, Faculty of Basic Science, University of Mazandaran, Babolsar, Iran.
Comput Biol Chem. 2023 Dec;107:107967. doi: 10.1016/j.compbiolchem.2023.107967. Epub 2023 Oct 6.
Aggregation of proteins is a biological phenomenon caused by misfolded proteins. Human superoxide dismutase (hSOD1) misfolding and aggregation underlie the neurological illness amyotrophic lateral sclerosis (ALS). The most significant contributing factor to ALS is genetic point mutations in SOD1. particularly, D101G mutant is the most harmful because it significantly reduces the life expectancy of patients. Subsequently, the use of natural polyphenolic flavonoids is strongly recommended to reduce the amyloidogenic behavior of protopathic proteins. In this study, using computational parameters such as protein-ligand interaction and molecular dynamics (MD) simulation analyses, we are trying to identify a pharmacodynamically promising flavonoid compound that can effectively inhibit the pathogenic behavior of the D101G mutant. Epigallocatechin-gallate (EGCG), Hesperidin, Isorhamnetin, and Diosmetin were identified as potential leads in a preliminary screening of flavonoids to anti-amyloid action. The results of MD showed that the binding of flavonoids to D101G mutant caused changes in stability, hydrophobicity of protein, and flexibility, as well as significantly led to the restoration of lost hydrogen bonds. Secondary structure analysis showed that protein destabilization and the increased propensity of β-sheet caused by the mutation were restored to the wild-type state upon binding of flavonoids. Besides, to differentiate aggregation, we elucidated alterations in the free energy landscape (FEL) and dynamic cross-correlation matrix (DCCM) of WT-SOD1 and mutant (unbound /bound) states. Among flavonoids, Epigallocatechin-gallate and Hesperidin had the most therapeutic efficacy against the D101G mutant. Therefore, Epigallocatechin-gallate and Hesperidin promise considerable therapeutic potential to develop highly effective inhibitors in reducing fatal and irreversible ALS.
蛋白质聚集是由错误折叠的蛋白质引起的一种生物学现象。人类超氧化物歧化酶（hSOD1）的错误折叠和聚集是神经疾病肌萎缩侧索硬化症（ALS）的基础。导致 ALS 的最重要因素是 SOD1 的遗传点突变，特别是 D101G 突变体，因为它会显著降低患者的预期寿命。因此，强烈建议使用天然多酚类黄酮来降低原纤维蛋白的淀粉样行为。在这项研究中，我们使用了蛋白质-配体相互作用和分子动力学（MD）模拟分析等计算参数，试图确定一种具有潜在药效的黄酮类化合物，该化合物可以有效抑制 D101G 突变体的致病行为。表没食子儿茶素没食子酸酯（EGCG）、橙皮苷、山奈素和圣草酚在黄酮类化合物抗淀粉样作用的初步筛选中被鉴定为潜在的先导化合物。MD 的结果表明，黄酮类化合物与 D101G 突变体的结合导致了蛋白质稳定性、疏水性和柔韧性的变化，并显著导致了丢失氢键的恢复。二级结构分析表明，结合黄酮类化合物后，突变引起的蛋白质不稳定和β-折叠倾向增加恢复到野生型状态。此外，为了区分聚集，我们阐明了自由能景观（FEL）和动态互相关矩阵（DCCM）在 WT-SOD1 和突变体（未结合/结合）状态下的变化。在黄酮类化合物中，表没食子儿茶素没食子酸酯和橙皮苷对 D101G 突变体的治疗效果最好。因此，表没食子儿茶素没食子酸酯和橙皮苷具有很大的治疗潜力，可以开发出高效的抑制剂来减少致命和不可逆转的 ALS。
