Molecular insight into amyloid oligomer destabilizing mechanism of flavonoid derivative 2-(4′ benzyloxyphenyl)-3-hydroxy-chromen-4-one through docking and molecular dynamics simulations

<p>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.</p

DNA Binding and Anti-Cancer Activity of Redox-Active Heteroleptic Piano-Stool Ru(II), Rh(III), and Ir(III) Complexes Containing 4‑(2-Methoxypyridyl)phenyldipyrromethene

The synthesis of four novel heteroleptic dipyrrinato complexes [(η⁶-arene)­RuCl­(2-pcdpm)] (η⁶-arene = C₆H₆, <b>1</b>; C₁₀H₁₄, <b>2</b>) and [(η⁵-C₅Me₅)­MCl­(2-pcdpm)] (M = Rh, <b>3</b>; Ir, <b>4</b>) containing a new chelating ligand 4-(2-methoxypyridyl)-phenyldipyrromethene (2-pcdpm) have been described. The complexes <b>1</b>–<b>4</b> have been fully characterized by various physicochemical techniques, namely, elemental analyses, spectral (ESI-MS, IR, ¹H, ¹³C NMR, UV/vis) and electrochemical studies (cyclic voltammetry (CV) and differential pulse voltammetry (DPV)). Structures of <b>3</b> and <b>4</b> have been determined crystallographically. In vitro antiproliferative and cytotoxic activity of these complexes has been evaluated by trypan blue exclusion assay, cell morphology, apoptosis, acridine orange/ethidium bromide (AO/EtBr) fluorescence staining, and DNA fragmentation assay in Dalton lymphoma (DL) cell lines. Interaction of <b>1</b>–<b>4</b> with calf thymus DNA (CT DNA) has also been supported by absorption titration and electrochemical studies. Our results suggest that in vitro antitumor activity of <b>1</b>–<b>4</b> lies in the order <b>2</b> > <b>1</b> > <b>4</b> > <b>3</b>