Anti-Neurodegenerating Activity: Structure–Activity Relationship Analysis of Flavonoids
Abstract
:1. Introduction
Why Focus on Flavonoids
2. Results and Discussion
2.1. Screening of Neurotrophic Activity of the Compounds
2.2. Validation of the Neurotrophic and Synaptogenic Activities of the Candidates
2.3. Determination of the Neuroprotective Activity
2.3.1. Oxidative Stress Model
2.3.2. Alzheimer’s Model
2.3.3. Parkinson’s Model
2.4. Structure–Activity Relationship (SAR) Analysis
2.4.1. Structure–Activity Relationship (SAR) Analysis Compared with Neuro-Differentiating Activity
2.4.2. Structure–Activity Relationship (SAR) Analysis Compared with Synaptogenic Activity
2.4.3. Structure–Activity Relationship (SAR) Analysis Compared with Antioxidant Activity
2.4.4. Structure–Activity Relationship (SAR) Analysis Compared with Anti-Inflammatory Activity
2.5. Molecular Docking Studies
2.5.1. Molecular Docking Studies with the TRKB-d5 Domain (PDB: 1HCF)
2.5.2. Additional Molecular Docking Studies with Human Phosphodiesterase 4B (PDB: 4MYQ) and AChE (PDB: 4BDT) and BuChE (PDB: 4BDS)
2.6. Pharmacophore Evaluation and ADMET Study
3. Materials and Methods
3.1. Origin of Compounds
3.2. Determination of the Highest Non-Toxic Dose of Compounds (Method S4.2)
3.3. Screening of Neurotrophic Activity of the Compounds (Method S4.3)
3.4. Assessment of the Neurotrophic and Synaptogenic Activities of the Candidates by High Content Screening (HCS) (Method S4.4)
3.5. Compound and Insult Treatment on Differentiated SH-SY5Y Cells (Method S4.5)
3.5.1. Assessment of Cell Viability and ROS Production (Method S4.5.1)
3.5.2. Investigation of Secretion of TNFα and IL-1β (Method S4.5.3)
3.6. Data Analysis and Visualisation
3.7. Molecular Docking Experiments
3.8. 3D Pharmacophore Model Generation and ADMET Study
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Compound | Ring A | Ring B | Docking Score (kcal/mol) | ||||
---|---|---|---|---|---|---|---|
C5 | C7 | C2′ | C3′ | C4′ | C5′ | ||
5 | OCH3 | OH | −9.5 | ||||
4 | OH | OH | OCH3 | OCH2CH3 | −8.4 | ||
23 | OH | OH | OH | OH | −9.4 |
Compound | Ring A | Ring B | Docking Score (kcal/mol) | ||||
---|---|---|---|---|---|---|---|
C5 | C7 | C2′ | C3′ | C4′ | C5′ | ||
5 | OCH3 | OH | −9.5 | ||||
5A | OCH3 | OCH3 | OH | −8.5 | |||
5B | OCH3 | OH | −8.8 | ||||
5C | OCH3 | OH | OH | −9.7 | |||
5D | OCH3 | OCH3 | OH | OH | −8.7 | ||
5E | OCH3 | OH | OH | −8.9 | |||
5F | OCH3 | OH | −9.4 | ||||
5G | OCH3 | OCH3 | OH | −8.3 | |||
5H | OCH3 | OH | −8.7 | ||||
5I | OCH3 | OH | OH | −9.6 | |||
5J | OCH3 | OCH3 | OH | OH | −8.6 | ||
5K | OCH3 | OH | OH | −9 | |||
5L | OCH3 | OH | OH | −9.5 | |||
5M | OCH3 | OCH3 | OH | OH | −8.6 | ||
5N | OCH3 | OH | OH | −9 | |||
5O | OCH3 | OH | OH | OH | −8.9 | ||
5P | OCH3 | OCH3 | OH | OH | OH | −8.4 | |
5Q | OCH3 | OH | OH | OH | −8.2 |
Docking Score (with -OCH3) on Ring A (kcal/mol) | Docking Score (Replacing -OCH3 with -OH) on Ring A (kcal/mol) |
---|---|
−9.7 | −9.6 |
−9.4 | −9.3 |
−9.6 | −9.5 |
−9.5 | −9.5 |
Compound | Ring A | Ring B | Docking Score (kcal/mol) | ||||
---|---|---|---|---|---|---|---|
C5 | C7 | C2′ | C3′ | C4′ | C5′ | ||
5 | OCH3 | OH | −10.2 | ||||
4 | OH | OH | OCH3 | OCH2CH3 | −8.9 | ||
23 | OH | OH | OH | OH | −10.0 |
Compound | Ring A | Ring B | Docking Score (kcal/mol) PDB:4BDT | Docking Score (kcal/mol) PDB:4BDS | ||||
---|---|---|---|---|---|---|---|---|
C5 | C7 | C2′ | C3′ | C4′ | C5′ | |||
5 | OCH3 | OH | −9.5 | −9.3 | ||||
4 | OH | OH | OCH3 | OCH2CH3 | −8.0 | −8.5 | ||
23 | OH | OH | OH | OH | −9.8 | −9.1 |
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Preet, G.; Haj Hasan, A.; Ramlagan, P.; Fawdar, S.; Boulle, F.; Jaspars, M. Anti-Neurodegenerating Activity: Structure–Activity Relationship Analysis of Flavonoids. Molecules 2023, 28, 7188. https://doi.org/10.3390/molecules28207188
Preet G, Haj Hasan A, Ramlagan P, Fawdar S, Boulle F, Jaspars M. Anti-Neurodegenerating Activity: Structure–Activity Relationship Analysis of Flavonoids. Molecules. 2023; 28(20):7188. https://doi.org/10.3390/molecules28207188
Chicago/Turabian StylePreet, Gagan, Ahlam Haj Hasan, Piteesha Ramlagan, Shameem Fawdar, Fabien Boulle, and Marcel Jaspars. 2023. "Anti-Neurodegenerating Activity: Structure–Activity Relationship Analysis of Flavonoids" Molecules 28, no. 20: 7188. https://doi.org/10.3390/molecules28207188