DCN1-UBE2M相互作用抑制剂的3D-QSAR、分子对接和分子动力学研究

Study on 3D-QSAR,Molecular Docking and Molecular Dynamics of DCN1-UBE2M Interaction Inhibitor

类泛素化是一种蛋白质翻译后修饰,其异常会导致神经退行性疾病和多种肿瘤的发生,因此它被视为有希望的抗肿瘤靶标。研究表明,抑制DCN1-UBE2M相互作用可选择性阻遏类泛素化。本文基于哌啶基脲类DCN1-UBE2M相互作用抑制剂进行3D-QSAR、分子对接和分子动力学模拟研究。利用3D-QSAR中的CoMFA和CoMSIA方法构建了相关模型,其交叉验证系数q^(2)分别为0.686、0.682,拟合验证系数r^(2)分别为0.966、0.931,表明模型是可靠的且预测能力较好。接着运用分子对接分析哌啶基脲类化合物与DCN1的相互作用,结果表明,它们主要通过氢键和疏水作用与靶蛋白结合。通过分子动力学模拟研究进一步了解结合模型和验证对接结果。本文所得的研究结果可为今后此类化合物的结构优化提供有效信息。

Neddylation is a post-translational modification of protein,and its abnormality can lead to neurodegenerative diseases and a variety of tumors which is therefore regarded as a promising anti-tumor target.Blockage of DCN1-UBE2 M interaction can selectively inhibit neddylation.In this paper,the study of 3 D-QSAR,molecular docking and molecular dynamics simulation studies were carried out on the piperidinylurea DCN1-UBE2 M interaction inhibitors.CoMFA and CoMSIA methods for 3 D-QSAR were used to build the models,whose cross-validation coefficients q^(2) were 0.686 and 0.682,and the fitting verification coefficients r^(2) were 0.966 and 0.931,respectively,indicating the reliability of the model and its good predictive ability.Furthermore,molecular docking was used to analyze the interaction of piperidinylurea compounds with DCN1,and the results showed that they mainly bind to the target protein through hydrogen bond interaction and hydrophobic interaction.Study on molecular dynamics simulation further understand the binding model and verify the docking results.These research provided clues for structural optimization of such compounds.