ORIGINAL RESEARCH article
Front. Chem.
Sec. Theoretical and Computational Chemistry
Volume 13 - 2025 | doi: 10.3389/fchem.2025.1569777
Inhibitory effect of Fisetin against the aggregation process of E100K SOD1 mutant: Computer-based drug design as a potential therapeutic for ALS disease
Provisionally accepted
Fatemeh Sadat Seyedi Asl1Nasrin Malverdi2
Fatemeh Sadat Ataei Kachouei3
Payam Baziyar4*Mohsen Nabi-Afjadi5- 1Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Alborz, Iran
- 2University of Isfahan, Isfahan, Isfahan, Iran
- 3Shiraz University, Shiraz, Fars, Iran
- 4University of Mazandaran, Babolsar, Iran
- 5Tarbiat Modares University, Tehran, Tehran, Iran
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Protein misfolding and aggregation in superoxide dismutase 1 (SOD1) are linked to the neurodegenerative disease amyotrophic lateral sclerosis (ALS). SOD1 mutations have a significant role in the pathophysiology and fast behavior of protopathic proteins in ALS illness.The E100K mutation may be useful in uncovering the pathogenic mechanism of SOD1 associated with ALS. According to several studies, giving small molecule inhibitors made from polyphenolic flavonoid compounds may be a viable treatment strategy for neurological conditions. Using molecular docking and MD simulations, we have identified a potential flavonoid drug that may successfully inhibit SOD1's amyloidogenic activity. Puerarin, Fisetin, and Peonidin provided intriguing pharmacological hints during the initial screening of flavonoids. The Fisetin-E100K complex had a larger residual energy contribution and substantial binding than other flavonoid compounds. The findings showed that, unlike other materials, Fisetin increased the structural stability, hydrophobicity, and flexibility of the mutant while reducing the amount of β-sheets. Furthermore, to distinguish aggregation in the mutant (unbound/bound) states, we displayed modifications in the free energy landscape (FEL). As a result, Fisetin was identified as having therapeutic potential against the E100K, which might make it a viable pharmacological option for the creation of inhibitors that lower the chance of ALS death.
Keywords: ALS, E100K mutant, SOD1 aggregation, Natural polyphenols, MD simulation, ADMET analysis
Received: 01 Feb 2025; Accepted: 28 Apr 2025.
Copyright: © 2025 Seyedi Asl, Malverdi, Ataei Kachouei, Baziyar and Nabi-Afjadi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Payam Baziyar, University of Mazandaran, Babolsar, Iran
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