Search

A central feature of a variety of related neurological disorders, including amyotrophic lateral sclerosis (ALS), is the deposition of misfolded protein aggregates in key regions of the human brain. Hence, targeting aggregation-prone SOD1 with small molecules can be used to design strategies to inhibit its aggregation. Based on molecular docking and molecular dynamics (MD) simulation, this study suggested that plant flavonoids can act as a potent anti-amyloidogenic polyphenol against SOD1 aggregation. Initial screening of flavonoids against protein aggregates identified Rosmarinic acid and Salvianolic acid A as promising drug leads that can effectively inhibit pathogenic behaviour. Our results showed that Salvianolic acid A reduces the β-sheet content and increases the structural stability, hydrophobicity, flexibility, and significantly the lost hydrogen bonds of the mutant compared to other compounds. Besides, we revealed changes in the free energy landscape (FEL) of WT-SOD1 and mutant states (unbound/bound) to differentiate aggregation. We deduced that the above-mentioned flavonoids can deviation the pathogenic behaviour of the D124 V mutant. Among them, Salvianolic acid A showed the greatest therapeutic potential against the D124 V mutant. Hence, Salvianolic acid A could serve as a drug candidate for the design of highly efficient inhibitors in reducing fatal and irreversible ALS. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Aggregation in the D101G mutant is a hallmark feature of ALS. • Hesperidin and Epigallocatechin-gallate restored the flexibility, H-bond, and conformation of D101G similar to WT-SOD1. • The 6β-sheet of D101G is prone to aggregation and is protected by polyphenolic flavonoids. • Polyphenolic flavonoids could be used as therapeutics for ALS. [ABSTRACT FROM AUTHOR]