Defining New Biological and Chemical Targets With Diazirines

药物化学涉及使用分子（药物）扰乱生物系统。这主要是通过形成短暂的小分子-蛋白质复合物来实现的，其中药物强烈且选择性地结合其蛋白质靶标。在疾病相关蛋白质和药物分子之间可预测地形成缔合复合物的能力是现代医学的基础，但首次鉴定出这种复合物（即发现其功能可以用药物样小分子或探针调节的新蛋白质结合口袋）在历史上是偶然完成的，通过用已知表型的分子进行靶点鉴定活动，或通过用预先验证的蛋白质靶点进行高通量筛选。正因为如此，我们基因组中的20，000个基因编码的蛋白质中只有不到500个获得了选择性靶向药物的批准。1现有的小分子疗法无法控制数千种额外的医学相关蛋白质。2化学生物学的基本目标之一是通过为人类蛋白质组的每个成员确定小分子调节剂来解决这一限制。3为了迎接这一巨大的挑战，我们提出的研究计划将利用双氮丙啶使能的复合物分子来寻找蛋白质结合伙伴，同时我们利用双氮丙啶使能的蛋白质来前景寻找小分子配体。与已建立的方案明显不同，我们将这样做，而不要求我们感兴趣的分子具有已知的表型活性。相反，我们认为，每一个具有“药物样”特征和足够程度的分子复杂性的分子都有一套与之结合最强的蛋白质。我们同样断言，识别假设蛋白质口袋的小分子配体是一项有价值的事业，可能会导致新的科学认识，即使口袋没有任何已知的调节功能。当然，当在疾病相关蛋白质中发现新的调控口袋时，这些调控口袋将立即用于药物开发。 因此，我们的研究将直接导致药物化学新的生物靶点的注释，并将同时提供新的先导化合物，结合这些目标，为未来的多个合作药物发现项目奠定基础。该计划代表了我们团队的一个大胆的新方向，但建立在有机合成，复杂分子表征，目标识别，化学生物学和我们团队在过去15年中获得的diazirine化学专业知识的基础上。与此同时，这项研究将使我们能够发展蛋白质组学和非经典氨基酸位点特异性结合的新技能。该计划将为高素质的人才提供一个肥沃的培训基地，使我的实验室能够建立在我们的成就指导和教学成功的科学家相当可观的记录。

Medicinal chemistry involves using molecules (drugs) to perturb biological systems. This mostly happens through formation of transient small-molecule-protein complexes, where a drug strongly and selectively binds to its protein target(s). The ability to predictably form association complexes between disease-relevant proteins and drug molecules underpins modern medicine, but identifying such complexes for the first time (i.e. discovering new protein binding pockets whose function can be regulated with drug-like small molecules or probes) has historically been done haphazardly, through target-identification campaigns with molecules of known phenotype or through high-throughput screens with pre-validated protein targets. Because of this, fewer than 500 of the proteins encoded by the 20,000 genes in our genome have approved drugs that selectively target them.1 Thousands of additional, medically relevant proteins cannot be controlled with existing small-molecule therapeutics.2 One of the foundational goals of chemical biology is to solve this limitation by identifying a small-molecule regulator for every member of the human proteome.2,3 To meet this grand challenge, our proposed research program will exploit diazirine-enabled complex molecules to search for protein binding partners at the same time as we exploit diazirine-enabled proteins to prospect for small molecule ligands. In a marked departure from established protocols, we will do so without any requirement for our molecules of interest to possess known phenotypic activity. Instead, we posit that every molecule possessing "drug-like" characteristics and a sufficient degree of molecular complexity will have a suite of proteins to which it binds most strongly. We likewise assert that the identification of small-molecule ligands for hypothesized protein pockets is a valuable undertaking that is likely to lead to new scientific understanding, even when that pocket does not have any known regulatory function. Of course, when new regulatory pockets are identified in disease-relevant proteins, these will have immediate utility for drug development. Our research will thus lead directly to the annotation of new biological targets for medicinal chemistry, and will simultaneously deliver new lead compounds that bind to those targets-setting the stage for multiple future collaborative drug discovery projects. This program represents a bold new direction for our group, yet builds upon expertise in organic synthesis, complex molecule characterization, target identification, chemical biology, and diazirine chemistry acquired by our team over the past 15 years. At the same time the research will allow us to develop new skills in proteomics, and in the site-specific incorporation of noncanonical amino acids. The program will provide a fertile training ground for highly qualified personnel, allowing my lab to build upon our considerable record of accomplishment mentoring and teaching successful scientists.