Molecular docking, molecular dynamics simulations and QSAR studies on some of 2-arylethenylquinoline derivatives for inhibition of Alzheimer's amyloid-beta aggregation: Insight into mechanism of interactions and parameters for design of new inhibitors

Alzheimer's disease is characterized using amyloid-beta (Aβ) aggregation. The present work was carried out to extend and design a novel quantitative structure-activity relationship (QSAR) model on inhibition efficiency of some of new 2-arylethenylquinoline derivatives against the Aβ_1-42 peptide aggregation. The QSAR study, molecular docking and molecular dynamics (MD) simulations were performed to explore the influence of the structural features and investigate the molecular mechanism of ligands interactions with the Aβ_1-42 peptide. Using molecular docking was understood that electron donating groups with small size help to create interactions between the ligands and peptide residues to stabilize the conformation of ligands at the binding pocket. QSAR model was developed using the most stable conformations and parameters that obtained from the molecular docking. It is shown that, a combination of docking parameters and structural descriptors of inhibitor compounds can describe the inhibition efficiency on Aβ_1-42 peptide. The model exhibited statistically significant results so that the coefficient of determination R²_train, Q²_LOO, R²_ext and GH (goodness of hit) are 0.912, 0.915, 0.836 and 0.804, respectively. The stability and binding modes of the compounds 1 and 13 with the most inhibition efficiency and compounds 12 and 36 with the lowest inhibition efficiency were determined by molecular dynamics simulations in GROMACS package. It is showed that interactions of compounds 1 and 13 are stable after 25ns of trajectories. Based on obtained results, 10 new drug compounds have been designed that provide better inhibition efficiency with the Aβ_1-42 peptide than the reference compounds.