Allium sativum‐Derived Alliin and Allicin Stably Bind to α‐Synuclein and Prevent Its Cytotoxic Aggregation
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| author | S. Rehan Ahmad Md. Zeyaullah Abdullah M. AlShahrani Khursheed Muzammil Adam Dawria Md. Faruque Ahmad Ahmed Salih |
| author_facet | S. Rehan Ahmad Md. Zeyaullah Abdullah M. AlShahrani Khursheed Muzammil Adam Dawria Md. Faruque Ahmad Ahmed Salih S. Rehan Ahmad Md. Zeyaullah Abdullah M. AlShahrani Khursheed Muzammil Adam Dawria Md. Faruque Ahmad Ahmed Salih |
| collection | Wiley Open Access |
| contents | Allium sativum‐Derived Alliin and Allicin Stably Bind to α‐Synuclein and Prevent Its Cytotoxic Aggregation S. Rehan Ahmad Md. Zeyaullah Abdullah M. AlShahrani Khursheed Muzammil Adam Dawria Md. Faruque Ahmad Ahmed Salih Proteins: Structure, Function, and Bioinformatics ABSTRACTNeurodegenerative diseases such as Parkinson's disease are characterized by the pathological aggregation of α‐synuclein. Targeting α‐synuclein aggregation through natural bioactive compounds offers a promising therapeutic strategy. In this study, sulfur‐containing compounds derived from Allium sativum were evaluated for their drug‐likeness, pharmacokinetic properties, and ability to inhibit α‐synuclein aggregation using a combination of in silico and in vitro approaches. ADMET profiling indicated high gastrointestinal absorption for nine compounds, supporting their drug‐like properties. Six compounds were predicted to cross the blood–brain barrier, suggesting potential efficacy in the central nervous system. Molecular docking identified alliin, allicin, E‐ajoene, and diallyl disulfide as top binders to α‐synuclein, forming stable interactions with key aggregation‐prone regions. Molecular dynamics simulations over 100 ns confirmed the structural stability of alliin– and allicin–α‐synuclein complexes, with minimal residue fluctuations and persistent hydrogen bonding. MM‐GBSA binding energy analysis corroborated these results, showing favorable binding free energies, particularly for alliin and E‐ajoene. Principal component analysis (PCA) further supported the role of alliin in stabilizing α‐synuclein dynamics. In vitro cellular assays further validated these computational findings. Using an SH‐SY5Y cell‐based α‐synuclein aggregation model, treatment with alliin and allicin significantly reduced α‐synuclein aggregation. Furthermore, MTT‐based cytotoxicity assays in SH‐SY5Y neuroblastoma cells overexpressing α‐synuclein revealed that alliin and allicin conferred notable cytoprotective effects by reducing α‐synuclein‐induced toxicity. Taken together, these findings highlight alliin and allicin as potent lead compounds that not only bind and stabilize α‐synuclein but also attenuate its aggregation and associated cytotoxicity. 10.1002/prot.70000 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| doi_str_mv | 10.1002/prot.70000 |
| format | Artículo Open Access |
| id | wiley_oa_10_1002_prot_70000 |
| institution | Wiley Open Access |
| license_str_mv | http://onlinelibrary.wiley.com/termsAndConditions#vor |
| publishDate | 2025 |
| publisher | Wiley |
| record_format | wiley_oa |
| spellingShingle | Allium sativum‐Derived Alliin and Allicin Stably Bind to α‐Synuclein and Prevent Its Cytotoxic Aggregation S. Rehan Ahmad Md. Zeyaullah Abdullah M. AlShahrani Khursheed Muzammil Adam Dawria Md. Faruque Ahmad Ahmed Salih Proteins: Structure, Function, and Bioinformatics Allium sativum‐Derived Alliin and Allicin Stably Bind to α‐Synuclein and Prevent Its Cytotoxic Aggregation S. Rehan Ahmad Md. Zeyaullah Abdullah M. AlShahrani Khursheed Muzammil Adam Dawria Md. Faruque Ahmad Ahmed Salih Proteins: Structure, Function, and Bioinformatics ABSTRACTNeurodegenerative diseases such as Parkinson's disease are characterized by the pathological aggregation of α‐synuclein. Targeting α‐synuclein aggregation through natural bioactive compounds offers a promising therapeutic strategy. In this study, sulfur‐containing compounds derived from Allium sativum were evaluated for their drug‐likeness, pharmacokinetic properties, and ability to inhibit α‐synuclein aggregation using a combination of in silico and in vitro approaches. ADMET profiling indicated high gastrointestinal absorption for nine compounds, supporting their drug‐like properties. Six compounds were predicted to cross the blood–brain barrier, suggesting potential efficacy in the central nervous system. Molecular docking identified alliin, allicin, E‐ajoene, and diallyl disulfide as top binders to α‐synuclein, forming stable interactions with key aggregation‐prone regions. Molecular dynamics simulations over 100 ns confirmed the structural stability of alliin– and allicin–α‐synuclein complexes, with minimal residue fluctuations and persistent hydrogen bonding. MM‐GBSA binding energy analysis corroborated these results, showing favorable binding free energies, particularly for alliin and E‐ajoene. Principal component analysis (PCA) further supported the role of alliin in stabilizing α‐synuclein dynamics. In vitro cellular assays further validated these computational findings. Using an SH‐SY5Y cell‐based α‐synuclein aggregation model, treatment with alliin and allicin significantly reduced α‐synuclein aggregation. Furthermore, MTT‐based cytotoxicity assays in SH‐SY5Y neuroblastoma cells overexpressing α‐synuclein revealed that alliin and allicin conferred notable cytoprotective effects by reducing α‐synuclein‐induced toxicity. Taken together, these findings highlight alliin and allicin as potent lead compounds that not only bind and stabilize α‐synuclein but also attenuate its aggregation and associated cytotoxicity. 10.1002/prot.70000 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| title | Allium sativum‐Derived Alliin and Allicin Stably Bind to α‐Synuclein and Prevent Its Cytotoxic Aggregation |
| topic | Proteins: Structure, Function, and Bioinformatics |
| url | https://onlinelibrary.wiley.com/doi/10.1002/prot.70000 |