Exploring the anti-amyloid potential of salvianolic acid A against the ALS-associated mutant SOD1: insights from molecular docking and molecular dynamic simulations

ABSTRACT

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.

KEYWORDS:

• ALS
• SOD1
• protein aggregation
• polyphenolic flavonoids
• molecular dynamics simulations

Acknowledgements

The authors would like to express their appreciation to the Research Council of Mazandaran University for its support during this project.

Disclosure statement

No potential conflict of interest was reported by the author(s).

CRediT authorship contribution statement

Zainab Abdullah waheed contributed to methodology, data curation, Validation, formal analysis, writing – original draft preparation, Bagher Seyedalipour and Abasalt Hosseinzadeh Colagar contributed to conceptualisation, supervision, methodology, validation, data curation, formal analysis, writing – review and editing. Payam Baziyar contributed to methodology, data curation, Validation, formal analysis, writing – original draft preparation, Project administration, writing – review, and editing.

Data availability

Data will be made available on request.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent to publish

The authors affirm that human research participants provided informed consent for publication.