Chemistry Department, Faculty of Science, Shahid Bahonar University of Kerman, Kerman, Iran; Young Researchers Society, Shahid Bahonar University of Kerman, Kerman, Iran.
Chemistry Department, Faculty of Science, Shahid Bahonar University of Kerman, Kerman, Iran.
J Mol Graph Model. 2019 Mar;87:129-143. doi: 10.1016/j.jmgm.2018.11.019. Epub 2018 Dec 4.
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 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 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 peptide. The model exhibited statistically significant results so that the coefficient of determination R, Q, R 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 peptide than the reference compounds.
阿尔茨海默病的特征是淀粉样蛋白-β（Aβ）聚集。本工作旨在扩展和设计一种新的定量构效关系（QSAR）模型，用于研究一些新型 2-芳基乙烯基喹啉衍生物对 Aβ肽聚集的抑制效率。通过 QSAR 研究、分子对接和分子动力学（MD）模拟，探讨了结构特征的影响，研究了配体与 Aβ肽相互作用的分子机制。通过分子对接发现，具有小尺寸的供电子基团有助于在配体和肽残基之间形成相互作用，从而稳定配体在结合口袋中的构象。QSAR 模型是使用从分子对接中获得的最稳定构象和参数开发的。结果表明，配体化合物的对接参数和结构描述符的组合可以描述对 Aβ肽的抑制效率。该模型显示出统计学上显著的结果，决定系数 R、Q、R 和 GH（命中良好）分别为 0.912、0.915、0.836 和 0.804。通过在 GROMACS 包中进行分子动力学模拟，确定了具有最高抑制效率的化合物 1 和 13 以及具有最低抑制效率的化合物 12 和 36 的稳定性和结合模式。结果表明，化合物 1 和 13 的相互作用在 25ns 的轨迹后是稳定的。基于获得的结果，设计了 10 种新的药物化合物，它们与参考化合物相比，对 Aβ 肽具有更好的抑制效率。
