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首页> 外文期刊>International Journal of Biological Macromolecules: Structure, Function and Interactions >Molecular dynamics simulation and 3D-pharmacophore analysis of new quinoline-based analogues with dual potential against EGFR and VEGFR-2
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Molecular dynamics simulation and 3D-pharmacophore analysis of new quinoline-based analogues with dual potential against EGFR and VEGFR-2

机译：新型喹啉基类似物对EGFR和VEGFR-2的基于喹啉类类似物的分子动力学模拟和3D-药物分析

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摘要

Epidermal growth factor and vascular endothelial growth factor-2 are important targets of tyrosine kinase for the treatment of various cancerous diseases. Combination of inhibition of both targets to produce synergy in the signal pathway is a critical approach to identify novel tyrosine kinase inhibitors. In this study, a series of new compounds derived from the 4-aminoquinoline as dual inhibitors were synthesized. The obtained results of cytotoxicity assay against human carcinoma cell lines indicated 0.8 mu M for 4c against A549 showing its high efficiency in comparison to erlotinib. Pharmacophore modeling as a structure-based method was investigated on dual inhibitors and 4c which was compared with co-crystallized in the active site of EGFR and VEGFR-2. They have shown the same binding orientation as vandetanib, erlotinib and sorafenib. Molecular dynamics simulation results approved that Met769, Lys721, Asp1046, and Lys868 are key residues in two binding sites for dual activity. Ala1050 and Pro968 were identified as new amino acid interaction sites for dual inhibition. 4c showed more favorable stability than vandetanib in VEGFR-2 receptor for a 50 ns dynamic simulation. The high correlation between essential pharmacophoric features of designed compounds and lead inhibitors interactions provided a deeper insight into the structural basis of 4-aminoquinoline inhibition. (C) 2019 Elsevier B.V. All rights reserved.
机译：表皮生长因子和血管内皮生长因子-2是酪氨酸激酶的重要靶标，用于治疗各种癌症疾病。在信号途径中产生协同作用的抑制作用的组合是鉴定新型酪氨酸激酶抑制剂的批判方法。在本研究中，合成了一系列从4-氨基喹啉衍生的新化合物作为双抑制剂。对于人癌细胞系的细胞毒性测定结果表明，对于A549，4C的0.8μmm表示其高效率与Erlotinib相比。在双重抑制剂和4C上研究了药物光线建模作为基于结构的方法，其与EGFR和VEGFR-2的活性位点中的共结晶进行比较。它们显示出与vandetanib，erlotinib和索拉非尼相同的结合取向。分子动力学仿真结果批准了MET769，LYS721，ASP1046和LYS868是双重活动的两个结合位点中的关键残留物。 ALA1050和PRO968被鉴定为新的氨基酸相互作用位点进行双重抑制。图4C显示了Vandetanib在VEGFR-2受体中比Vandetanib更有利的稳定性，用于50ns动态模拟。设计化合物的基本药物特征与铅抑制剂相互作用的高度相关性提供了对4-氨基喹啉抑制的结构基础的更深层次的洞察力。 （c）2019 Elsevier B.v.保留所有权利。

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