title: Molecular insight into amyloid oligomer destabilizing mechanism of flavonoid derivative 2-(4' benzyloxyphenyl)-3-hydroxy-chromen-4-one through docking and molecular dynamics simulations.
abstract: Aggregation of amyloid peptide (Aβ) has been shown to be directly related to progression of Alzheimer's disease (AD). Aβ is neurotoxic and its deposition and aggregation ultimately lead to cell death. In our previous work, we reported flavonoid derivative (compound 1) showing promising result in transgenic AD model of Drosophila. Compound 1 showed prevention of Aβ-induced neurotoxicity and neuroprotective efficacy in Drosophila system. However, mechanism of action of compound 1 and its effect on the amyloid is not known. We therefore performed molecular docking and atomistic, explicit-solvent molecular dynamics simulations to investigate the process of Aβ interaction, inhibition, and destabilizing mechanism. Results showed different preferred binding sites of compound 1 and good affinity toward the target. Through the course of 35 ns molecular dynamics simulation, conformations_5 of compound 1 intercalates into the hydrophobic core near the salt bridge and showed major structural changes as compared to other conformations. Compound 1 showed interference with the salt bridge and thus reducing the inter strand hydrogen bound network. This minimizes the side chain interaction between the chains A-B leading to disorder in oligomer. Contact map analysis of amino acid residues between chains A and B also showed lesser interaction with adjacent amino acids in the presence of compound 1 (conformations_5). The study provides an insight into how compound 1 interferes and disorders the Aβ peptide. These findings will further help to design better inhibitors for aggregation of the amyloid oligomer.
authors.affiliation: a Biotechnology Division , CSIR-Central Institute of Medicinal and Aromatic Plants , P.O. - CIMAP, Near Kukrail Picnic Spot, Lucknow 226015 , Uttar Pradesh , India.
authors.forename: Akhil
authors.initials: A
authors.lastname: Kumar
authors.affiliation: a Biotechnology Division , CSIR-Central Institute of Medicinal and Aromatic Plants , P.O. - CIMAP, Near Kukrail Picnic Spot, Lucknow 226015 , Uttar Pradesh , India.
authors.forename: Swati
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: a Biotechnology Division , CSIR-Central Institute of Medicinal and Aromatic Plants , P.O. - CIMAP, Near Kukrail Picnic Spot, Lucknow 226015 , Uttar Pradesh , India.
authors.forename: Shubhandra
authors.initials: S
authors.lastname: Tripathi
authors.affiliation: b Faculty of Science, Department of Biochemistry , Banaras Hindu University , Varanasi 221005 , Uttar Pradesh , India.
authors.forename: Sandeep Kumar
authors.initials: SK
authors.lastname: Singh
authors.affiliation: b Faculty of Science, Department of Biochemistry , Banaras Hindu University , Varanasi 221005 , Uttar Pradesh , India.
authors.forename: Saripella
authors.initials: S
authors.lastname: Srikrishna
authors.affiliation: a Biotechnology Division , CSIR-Central Institute of Medicinal and Aromatic Plants , P.O. - CIMAP, Near Kukrail Picnic Spot, Lucknow 226015 , Uttar Pradesh , India.
authors.forename: Ashok
authors.initials: A
authors.lastname: Sharma
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D003198:Computer Simulation; D005419:Flavonoids / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D066329:Protein Aggregates / Q000187:drug effects; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D055503:Protein Multimerization / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects
chemical_list: D000682:Amyloid; D005419:Flavonoids; D066329:Protein Aggregates
keywords: Alzheimer’s; amyloid oligomer; docking; flavonoid derivatives; molecular dynamics simulation