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首页> 外文期刊>Journal of the Taiwan Institute of Chemical Engineers >Combined pharmacophore-guided 3D-QSAR, molecular docking and molecular dynamics studies for evodiamine analogs as DNA topoisomerase I inhibitors
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Combined pharmacophore-guided 3D-QSAR, molecular docking and molecular dynamics studies for evodiamine analogs as DNA topoisomerase I inhibitors

机译：综合药扫描引导的3D-QSAR，分子对接和用于Evodiamine类似物的分子动力学研究作为DNA拓扑异构酶I抑制剂

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DNA topoisomerase I (TopoI) is a new important anti-cancer drug target. Pharmacophore, 3D-QSAR, molecular docking and molecular dynamics studies were used to reveal structural and chemical features essential for evodiamine and designing/screening novel and potent inhibitors. The best pharmacophore model consists of four hydrophobic interaction sites and three hydrogen bond receptors. 60 evodiamine analogs were used for constructing the best comparative molecular field analysis (CoMFA, q(2) = 0.729, r(2) = 0.985) and comparative molecular similarity index analysis (CoMSIA, q(2) = 0.746, r(2) = 0.989) models, the models had high predictive ability, and the contour map was in good agreement with the generated pharmacophore features. Through virtual screening and structure-activity relationship (SAR), we obtained ten(DS1-8, z1-2) well predicted compounds. By molecular docking and molecular dynamics, we found the electrostatic field had the greatest influence on the residues ASN722 and THR718 in the DNA minor groove and the molecular structure should be planarized and appropriate in this region. The hydrogen bond produced by the inhibitor with the residues GLU356 and ARG364 and the hydrophobic interaction with base TGP11, DA113 play an important role in protein stability of the inhibitors. Results provide favorable theoretical foundation for further structural optimization, design, and synthesis of novel DNA Topol inhibitor. (C) 2017 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved.
机译：DNA拓扑异构酶I（Topoi）是一种新的重要抗癌药物目标。药镜，3D-QSAR，分子对接和分子动力学研究旨在揭示Evodiamine和设计/筛选新颖和有效抑制剂所必需的结构和化学特征。最佳的药效线模型由四个疏水性相互作用位点和三个氢键受体组成。 60个Evodiamine类似物用于构建最佳的对比分子场分析（COMFA，Q（2）= 0.729，R（2）= 0.985）和比较分子相似性指数分析（COMSIA，Q（2）= 0.746，R（2） = 0.989）型号，模型具有高的预测能力，轮廓图与所生成的药效线特征很好。通过虚拟筛选和结构 - 活动关系（SAR），我们获得了十（DS1-8，Z1-2）良好预测的化合物。通过分子对接和分子动力学，我们发现静电场对DNA小凹槽中的残留物Asn722和Thr718对残留物的影响最大，并且分子结构应该在该区域中平坦化和适当。抑制剂与残留物GLU356和ARG364产生的氢键和与基础TGP11的疏水相互作用，DA113在抑制剂的蛋白质稳定性中起重要作用。结果为进一步的结构优化，设计和合成提供了良好的理论基础，新型DNA拓扑抑制剂。 （c）2017台湾化工工程师研究所。 elsevier b.v出版。保留所有权利。

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