整合蛋白与抑制剂设计
发布时间：2019-07-10 19:17
【摘要】：整合蛋白是一类重要的细胞表面黏附分子,由α和β亚基以非共价键结合而形成的异二聚体糖蛋白,对免疫反应、免疫细胞的组织定位、凝血、组织愈伤、癌细胞转移和新血管生成以及骨重塑等都至关重要。整合蛋白的功能依赖于对其配体结合的亲和性,以及所介导的下游信号通路。目前,对整合蛋白构象调节及亲和力调控机制已有深入了解。人类24种整合蛋白中,已有3种整合蛋白作为临床治疗靶点。这些药物以单克隆抗体、多肽和小分子化合物为主,均针对配体识别序列而设计。该类抑制剂往往具有部分激活的作用,直接导致药物的副反应和毒性。为了改善第一代整合蛋白药物的不足,目前基于晶体结构研究、虚拟筛选、高通量筛选以及基于结构设计的新型整合蛋白抑制剂,已经有许多进入临床试验。本文综述了一系列晶体结构中蛋白质与抑制剂的相互作用,以及借助晶体结构获得纯抑制剂为目的的实例,这些策略将会对开发新型有效的整合蛋白抑制剂提供很好的参考。
[Abstract]:Integrin is an important class of cell surface adhesion molecules. Heterodimeric glycoproteins formed by non-covalent binding of 伪 and 尾 subunits are very important for immune response, tissue localization, coagulation, tissue healing, cancer cell metastasis and neovascularization, and bone remodeling. The function of integrated protein depends on the affinity to its ligand binding and the downstream signal pathway mediated by it. At present, the conformational regulation and affinity regulation mechanism of integrated protein have been deeply understood. Of the 24 human integrins, 3 have been used as clinical therapeutic targets. These drugs are mainly monoclonal antibodies, peptides and small molecular compounds, all of which are designed for ligand recognition sequences. These inhibitors often have the effect of partial activation, which directly leads to the side effects and toxicity of drugs. In order to improve the shortcomings of the first generation of integrated protein drugs, many new integrated protein inhibitors based on crystal structure research, virtual screening, high throughput screening and structural design have been involved in clinical trials. In this paper, a series of interactions between proteins and inhibitors in crystal structures are reviewed, and some examples of obtaining pure inhibitors by means of crystal structures are reviewed. These strategies will provide a good reference for the development of new and effective integrated protein inhibitors.
【作者单位】： 绍兴文理学院医学院医学实验中心;宁波大学应用海洋生物技术教育部重点实验室;
【基金】：国家自然科学基金(No.20903058;No.40906080) 绍兴文理学院项目(No.2015LG1011) 浙江省教育厅项目(No.Y201635696)资助~~
【分类号】：R91
本文编号：2512827
[Abstract]:Integrin is an important class of cell surface adhesion molecules. Heterodimeric glycoproteins formed by non-covalent binding of 伪 and 尾 subunits are very important for immune response, tissue localization, coagulation, tissue healing, cancer cell metastasis and neovascularization, and bone remodeling. The function of integrated protein depends on the affinity to its ligand binding and the downstream signal pathway mediated by it. At present, the conformational regulation and affinity regulation mechanism of integrated protein have been deeply understood. Of the 24 human integrins, 3 have been used as clinical therapeutic targets. These drugs are mainly monoclonal antibodies, peptides and small molecular compounds, all of which are designed for ligand recognition sequences. These inhibitors often have the effect of partial activation, which directly leads to the side effects and toxicity of drugs. In order to improve the shortcomings of the first generation of integrated protein drugs, many new integrated protein inhibitors based on crystal structure research, virtual screening, high throughput screening and structural design have been involved in clinical trials. In this paper, a series of interactions between proteins and inhibitors in crystal structures are reviewed, and some examples of obtaining pure inhibitors by means of crystal structures are reviewed. These strategies will provide a good reference for the development of new and effective integrated protein inhibitors.
【作者单位】： 绍兴文理学院医学院医学实验中心;宁波大学应用海洋生物技术教育部重点实验室;
【基金】：国家自然科学基金(No.20903058;No.40906080) 绍兴文理学院项目(No.2015LG1011) 浙江省教育厅项目(No.Y201635696)资助~~
【分类号】：R91
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，本文编号：2512827
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