杂环并吡啶酮类HIV-1整合酶抑制剂的设计、合成及构效关系研究

项目名称： 杂环并吡啶酮类HIV-1整合酶抑制剂的设计、合成及构效关系研究

项目编号： No.21272020

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 数理科学和化学

项目作者： 胡利明

作者单位： 北京工业大学

项目金额： 80万元

中文摘要： HIV-1整合酶在病毒复制过程中发挥重要作用，是设计艾滋病治疗药物的理想靶标。本项目在前期工作基础上提出新型杂环并吡啶酮衍生物作为整合酶抑制剂，探索该类化合物的合成方法，通过研究环上杂原子以及取代基的改变对活性的影响，阐明化合物结构与活性之间的相互关系，发展快速准确的预测整合酶抑制剂结构模型。主要包括：设计合成杂环并吡啶酮类化合物；通过用分子对接方法、分子动力学模拟和结合自由能计算等方法，对整合酶与抑制剂可能结合靶位和结合模式进行预测；针对抗性病毒株整合酶突变特点，设计并合成对抗性病毒株有效果的化合物；完善分子水平和细胞水平活性测定方法，利用QSAR方法研究给体-受体相互作用方式，探索小分子配体与受体间的化学适配性，提出抑制剂结构优化的方向。该项目不仅为作用机理提供理论依据，而且为基于受体结构的HIV-1整合酶抑制剂设计提供实验依据。

中文关键词： 人类免疫缺陷病毒；整合酶抑制剂；哌啶杂环衍生物；活性测试方法；构效关系

英文摘要： HIV-1 integrase is indispensabbe for HIV-1 replication and has become a validated target for developing anti-AIDS agents.In our previous works,polyphenol compounds were identified as integrase inhibitors,but some of them showed weak antiviral activity.In order to develop effective integrase inhibitors, substituted hetero-pyridinones were designed as high selectivity for the strand transfer reaction.The compounds have a polar coplanar moiety,which ia assumed to chelate two magnesium ions in binding site.The project will focus on three key scientific issues that are design and synthesis of lead compounds, improvement on assay methods and quantitative structure-activity relationship(QSAR).The first, we will develop a new synthetic route to the hetero-pyridnone derivatives and illustrate impacts on electron dispensation on the heterocycle skeleton for various hetero-atom. The second, assessing the compounds anti-HIV activity based on biochemical and cellular assay and exploring the mechanism that lead compounds inhibit integrase, especially integrase mutations. Finally, CoMFA and CoMSIA,were applied to these compounds to gain insights into the key structural factors affecting the bioactivity of these compounds. To construct more reasonable 3D-SAR models,we will adopt two different conformer-based alignment methods a

英文关键词： HIV-1；Integrase Inhibitors；Pyridino heterocyclic derivatives；Bioactivity Assay；SAR