Defining New Biological and Chemical Targets With Diazirines

药物化学包括使用分子（药物）来扰乱生物系统。这主要是通过瞬间小分子蛋白复合物的形成而发生的，在这个过程中，药物会选择性地与它的蛋白靶标紧密结合。在疾病相关蛋白和药物分子之间形成可预测的关联复合物的能力是现代医学的基础，但首次识别这种复合物（即发现新的蛋白质结合口袋，其功能可以用药物样的小分子或探针来调节）在历史上一直是偶然完成的，通过已知表型分子的靶标识别活动或通过预先验证的蛋白质靶标的高通量筛选。正因为如此，我们基因组中2万个基因编码的蛋白质中，只有不到500种被批准了选择性靶向它们的药物现有的小分子疗法无法控制数以千计的其他医学上相关的蛋白质化学生物学的基本目标之一就是通过为人类蛋白质组的每个成员确定一个小分子调节因子来解决这一限制为了应对这一巨大挑战，我们提出的研究计划将利用重氮嘧啶激活的复杂分子来寻找蛋白质结合伙伴，同时我们利用重氮嘧啶激活的蛋白质来寻找小分子配体。在与既定方案的明显背离中，我们将在不要求我们感兴趣的分子具有已知表型活性的情况下这样做。相反，我们假设每个具有“类药物”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紧密的蛋白质。我们同样认为，鉴定假设的蛋白质口袋的小分子配体是一项有价值的工作，可能会导致新的科学理解，即使那个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的新生物靶点的注释，并将同时提供与这些靶点结合的新先导化合物-为未来多个合作药物发现项目奠定基础。这个项目代表了我们团队的一个大胆的新方向，但建立在我们团队在过去15年中获得的有机合成，复杂分子表征，靶标鉴定，化学生物学和重氮化学方面的专业知识基础上。与此同时，这项研究将使我们在蛋白质组学和非规范氨基酸的位点特异性结合方面发展新的技能。该项目将为高素质人才提供肥沃的培训场地，使我的实验室能够在指导和教授成功科学家的可观成就的基础上再接再厉。

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.