化学生物学和药物发现是两种追求不同目标但相辅相成的科学活动。前者是一门介入性科学,旨在通过用为此目的设计的化合物调节其分子成分来理解生命系统。后者是设计候选药物的艺术,即,作用于人类选定分子成分并显示的分子,作为候选治疗,最佳可达风险收益比。在化学生物学中,化合物是理解生物学的手段,而在药物发现中,化合物是目标。他们分享的工具箱包括生物和化学分析技术,细胞和全身成像,并通过最先进的设计和合成工具探索化学空间。在这篇文章中,我们通过从我们研究所过去十年进行的研究项目中选取的一些例子,研究了药物发现和化学生物学共享的几种工具。这些例子说明了化学探针和工具的设计,以识别和验证新的目标,量化体外和体内的目标参与,发现命中并优化药代动力学特性,同时在空间和时间上控制生物系统各个生物相中的化合物浓度。
Chemical biology and drug discovery are two scientific activities that pursue different goals but complement each other. The former is an interventional science that aims at understanding living systems through the modulation of its molecular components with compounds designed for this purpose. The latter is the art of designing drug candidates, i.e., molecules that act on selected molecular components of human beings and display, as a candidate treatment, the best reachable risk benefit ratio. In chemical biology, the compound is the means to understand biology, whereas in drug discovery, the compound is the goal. The toolbox they share includes biological and chemical analytic technologies, cell and whole-body imaging, and exploring the chemical space through state-of-the-art design and synthesis tools. In this article, we examine several tools shared by drug discovery and chemical biology through selected examples taken from research projects conducted in our institute in the last decade. These examples illustrate the design of chemical probes and tools to identify and validate new targets, to quantify target engagement in vitro and in vivo, to discover hits and to optimize pharmacokinetic properties with the control of compound concentration both spatially and temporally in the various biophases of a biological system.