基于分子原型和分子探针的药用活性分子蛋白作用靶标研究  

Protein targets of medicinally active molecules based on their original structures and molecular probes

作　　者：杨婉琪 张崇敬 YANG Wan-qi;ZHANG Chong-jing(State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China)

机构地区：[1]中国医学科学院、北京协和医学院药物研究所,天然产物活性物质与功能国家重点实验室,北京100050

出　　处：《药学学报》2020年第7期1439-1452,共14页Acta Pharmaceutica Sinica

基　　金：中国医学科学院医学与健康科技创新工程(2017-I2M-4-005)。

摘　　要：药用活性分子是药物活性的载体和实施者。研究它们的蛋白作用靶标不但能够阐明其作用机制而且能够加深研究人员对生物体系的理解。本文综述了一些在临床使用的药物分子和在研活性分子的蛋白作用靶标,它们具有抗炎、抗疟、抗肿瘤等生物活性。研究方法侧重于两种化学蛋白质组学方法:基于活性的蛋白质组学分析和细胞热迁移分析。基于活性的蛋白质组学分析利用修饰活性分子后得到的分子探针来了解化合物与靶标之间的相互作用机制,可用于识别小分子的蛋白质靶标。细胞热迁移分析,不必对活性分子进行任何化学修饰,而是利用活性分子与靶标蛋白结合后提高了蛋白的热稳定性,结合定量蛋白质组学方法实现靶标蛋白的发现。这两种方法互为补充,能够有效阐明药用分子的蛋白作用靶标,发现其药效作用机制、揭示其毒性作用机制、发现新型的药用靶标,最终推动药物研发的进程。Medicinally active molecules are those that have pharmacological effects.Research on protein targets of these molecules not only clarifies their mechanism of action,but also deepens our understanding of biological systems.Here we review recent advances in protein targets of drugs used in clinical practice or in preclinical research.They have various functions including anti-inflammatory,anti-malarial,anti-tumor and other biological activities.Activity-based protein profiling(ABPP)and cellular thermal shift assay(CETSA)are two useful methods to identify the protein targets of small molecules.ABPP depends on a derivative active molecule probe to pull down the protein targets to reveal the interaction mechanisms between the active molecules and targets.Drug target engagement also can be assessed by means of CETSA based on ligand-induced changes in protein thermal stability.In the CETSA approach,the active molecules do not need to be chemically modified.Combining the CETSA method with quantitative mass spectrometry is an effective approach to study the effect of compounds on the thermal profile of a cellular proteome and identify the protein targets.ABPP and CETSA can be complementary and effectively clarify the protein targets.The study of protein targets will help reveal the mechanism of action of medicinal molecules,reveal toxic mechanisms and aid in the discovery of new medicinal targets to promote the process of drug development.

关 键 词：化学蛋白质组学 活性分子探针 细胞热迁移分析 靶点探索 药物开发 

分 类 号：R916[医药卫生—药学]