Inhibitory effect of Fisetin against the aggregation process of SOD1 E100K mutant: computer-based drug design as a potential therapeutic for ALS disease
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 usefu...
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Frontiers Media S.A.
2025-05-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2025.1569777/full |
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| author | Fatemeh Sadat Seyedi Asl Nasrin Malverdi Fatemeh Sadat Ataei Kachouei Fatemeh Zarei Shamim Ghiabi Payam Baziyar Mohsen Nabi-Afjadi |
| author_facet | Fatemeh Sadat Seyedi Asl Nasrin Malverdi Fatemeh Sadat Ataei Kachouei Fatemeh Zarei Shamim Ghiabi Payam Baziyar Mohsen Nabi-Afjadi |
| author_sort | Fatemeh Sadat Seyedi Asl |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d5acb1fb9bb445ac8478f2a215358e29 |
| institution | Kabale University |
| issn | 2296-2646 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Chemistry |
| spelling | doaj-art-d5acb1fb9bb445ac8478f2a215358e292025-08-20T03:47:34ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462025-05-011310.3389/fchem.2025.15697771569777Inhibitory effect of Fisetin against the aggregation process of SOD1 E100K mutant: computer-based drug design as a potential therapeutic for ALS diseaseFatemeh Sadat Seyedi Asl0Nasrin Malverdi1Fatemeh Sadat Ataei Kachouei2Fatemeh Zarei3Shamim Ghiabi4Payam Baziyar5Mohsen Nabi-Afjadi6Medical School, Tehran University of Medical Sciences, Tehran, IranDepartment of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, IranDepartment of Biology, Shiraz University, Shiraz, IranDepartment of Biology, Islamic Azad University, Arsanjan, IranDepartment of Medical Chemistry, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, IranDepartment of Molecular and Cell Biology, Faculty of Basic Science, University of Mazandaran, Babolsar, IranDepartment of Biochemistry, Faculty of Biological Sciences, University of Tarbiat Modares, Tehran, IranProtein 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.https://www.frontiersin.org/articles/10.3389/fchem.2025.1569777/fullALSE100K mutantSOD1 aggregationnatural polyphenolsMD simulationADMET analysis |
| spellingShingle | Fatemeh Sadat Seyedi Asl Nasrin Malverdi Fatemeh Sadat Ataei Kachouei Fatemeh Zarei Shamim Ghiabi Payam Baziyar Mohsen Nabi-Afjadi Inhibitory effect of Fisetin against the aggregation process of SOD1 E100K mutant: computer-based drug design as a potential therapeutic for ALS disease Frontiers in Chemistry ALS E100K mutant SOD1 aggregation natural polyphenols MD simulation ADMET analysis |
| title | Inhibitory effect of Fisetin against the aggregation process of SOD1 E100K mutant: computer-based drug design as a potential therapeutic for ALS disease |
| title_full | Inhibitory effect of Fisetin against the aggregation process of SOD1 E100K mutant: computer-based drug design as a potential therapeutic for ALS disease |
| title_fullStr | Inhibitory effect of Fisetin against the aggregation process of SOD1 E100K mutant: computer-based drug design as a potential therapeutic for ALS disease |
| title_full_unstemmed | Inhibitory effect of Fisetin against the aggregation process of SOD1 E100K mutant: computer-based drug design as a potential therapeutic for ALS disease |
| title_short | Inhibitory effect of Fisetin against the aggregation process of SOD1 E100K mutant: computer-based drug design as a potential therapeutic for ALS disease |
| title_sort | inhibitory effect of fisetin against the aggregation process of sod1 e100k mutant computer based drug design as a potential therapeutic for als disease |
| topic | ALS E100K mutant SOD1 aggregation natural polyphenols MD simulation ADMET analysis |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2025.1569777/full |
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