Discovery of a tetracyclic indole alkaloid that postpones fibrillation of hen egg white lysozyme protein

Ashrafian, H ; Sharif University of Technology | 2021

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  1. Type of Document: Article
  2. DOI: 10.1016/j.ijbiomac.2021.05.212
  3. Publisher: Elsevier B.V , 2021
  4. Abstract:
  5. Protein aggregation, such as amyloid fibril formation, is molecular hallmark of many neurodegenerative disorders including Alzheimer's, Parkinson's, and Prion disease. Indole alkaloids are well-known as the compounds having the ability to inhibit protein fibrillation. In this study, we experimentally and computationally have investigated the anti-amyloid property of a derivative of a synthesized tetracyclic indole alkaloid (TCIA), possessing capable functional groups. The fibrillation reaction of Hen White Egg Lysozyme (HEWL) was performed in absence and presence of the indole alkaloid. For quantitative analysis, we used Thioflovin T binding assay which showed ~50% reduction in fibril formation in the presence of 20 μM TCIA. Using TEM imaging, we observed a significant morphological change in our model protein in the presence of TCIA. In addition, we exploited FT-IR assay by which Amide I peak's shifting toward lower wavenumber was clearly observed. Using Molecular Docking, the interaction of the inhibitor (TCIA) with the protein's amyloidogenic region was modeled. Also, different biophysical parameters were calculated by Molecular Dynamics (MD) simulation. Various biochemical assays, conformational change, and hydrophobicity exposure of the protein during amyloid formation indicated that the compound assists HEWL to keep its native structure via destabilizing β-sheet structure. © 2021
  6. Keywords:
  7. Adrenochrome ; Besipirdine ; Egg white ; Etodolac ; Fendosal ; Indole alkaloid ; Indometacin ; Lysozyme ; Pindolol ; Sumatriptan ; Tetracyclic indole alkaloid ; Unclassified drug ; Benzothiazole derivative ; Hen egg lysozyme ; Protein aggregate ; Thioflavine ; Beta sheet ; Binding assay ; Collagen fibril ; Controlled study ; Drug development ; Drug mechanism ; Drug structure ; Drug synthesis ; Exposure ; Fourier transform infrared spectroscopy ; Hen ; Hydrophobicity ; Molecular docking ; Molecular dynamics ; Nonhuman ; Quantitative analysis ; Transmission electron microscopy ; Animal ; Chemical phenomena ; Chemistry ; Chicken ; Drug effect ; Infrared spectroscopy ; Protein secondary structure ; Animals ; Benzothiazoles ; Chickens ; Enzyme stability ; Hydrophobic and hydrophilic interactions ; Indole alkaloids ; Molecular docking simulation ; Molecular dynamics simulation ; Muramidase ; Protein aggregates ; Protein structure, secondary ; Spectroscopy, fourier transform infrared
  8. Source: International Journal of Biological Macromolecules ; Volume 183 , 2021 , Pages 1939-1947 ; 01418130 (ISSN)
  9. URL: https://www.sciencedirect.com/science/article/abs/pii/S014181302101196X