| 张玲,刘鹰翔,赵钟祥,蔡晓力,马玉卓.化学通报,2018,81(2):148-157. |
| 由3D-QSAR、分子对接和分子动力学模拟研究吲唑类化合物与PI3Kδ抑制剂的相互作用 |
| Study on the Interation of Indazole Derivatives with PI3Kδ Inhibitors by 3D-QSAR、Docking and Molecular Dynamics Simulation |
| 投稿时间：2017-09-29 修订日期：2017-11-27 |
| DOI： |
| 中文关键词: PI3Kδ 分子对接 三维定量构效关系 分子动力学模拟 |
| 英文关键词:PI3Kδ molecular docking 3D-QSAR molecular dynamics simulation |
| 基金项目:国家自然科学基金项目（81270054）和 广东省高等学校优秀青年教师培养计划(Yq2013045) |
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| 中文摘要: |
| 磷酸肌醇3-激酶 δ (PI3Kδ)参与慢性阻塞性肺疾病的炎性过程并且被鉴定为一个新的潜在治疗靶点。本文采用三维定量构效关系(3D-QSAR)、分子对接和分子动力学研究了47个吲唑类化合物与P13Kδ激酶的相互作用，并建立了相应的模型。其中，比较分子场分析(CoMFA)模型q2=0.719，r2=0.972；比较分子相似性指数分析(CoMSIA)模型q2=0.649，r2=0.983，表明所建的QSAR模型具有稳定可靠的预测能力。CoMFA和CoMSIA等势图形象的描述了不同的场效应对活性的影响，其中立体场、疏水场及氢键受体场对活性有较大的贡献。接着采用分子对接探索小分子化合物与P13Kδ的结合模式，结合模式显示吲唑类化合物主要通过氢键作用与疏水作用与P13Kδ紧密结合，并且通过分子动力学模拟进一步验证了对接结果。最后根据等势图、对接模式和分子动力学模拟获取的信息设计了8个高活性的PI3Kδ抑制剂。 |
| 英文摘要: |
| Phosphoinositide 3-kinase delta (PI3Kδ) is involved in inflammatory process of chronic obstructive pulmonary disease (COPD) and has been identified a new potential therapeutic target. In this paper, three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics were used to study the interaction between 47 indazole derivatives and P13Kδ, and corresponding models were established. The comparative molecular field analysis (CoMFA) model q2=0.719, r2=0.972, comparative molecular similarity index analysis (CoMSIA) model q2=0.649, r2=0.983, indicating that constructed QSAR models have stable and reliable predictive ability. CoMFA and CoMSIA contour maps visual describe the effect of different fields on activity, the steric, hydrophobic and hydrogen bond acceptor field have greater contribution to the activity. Then, the binding mode of small molecule and P13Kδ was explored by molecular docking. The binding model showed that indazole compounds were mainly bound to P13Kδ by hydrogen bonding and hydrophobic interaction, and the results of docking were further verified by molecular dynamics simulation. Finally, eight highly active PI3Kδ inhibitors were designed based on the information obtained from the contour maps, docking mode and molecular dynamics simulation. |
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