Establishing pharmacophore-centric proteome-wide structure-affinity relationships by chemical proteomics (ChemProtSAR)

已经非常清楚的是，大多数治疗药物调节不止一种蛋白质的功能。因此，根据药物的其他靶点，将药物重新用于新的医学适应症已成为一种机会主义但成功的概念。然而，大多数情况下，这些新的活性仅在使用多年后才被确定，因为目前的药物发现方法从未研究过特定药物或潜在药效团的全部潜力。化学蛋白质组学已经成为一种主要的方法来描绘小分子的目标谱，而无需先验假设，我们已经开发了有效的工作流程来系统地揭示临床研究药物的药物再利用机会。在这个新的跨学科研究计划中，我们将联合收割机结合药物化学，生物化学，质谱和生物信息学，建立一个以药效团为中心的药物发现方法，系统地研究蛋白质组范围内任何给定小分子的靶空间，以建立其结构-亲和力关系（SAR）。更具体地，我们将测量和比较基于相同化学支架的一百个结构相关分子的小文库的靶谱，所述相同化学支架具有已知的激酶和溴结构域抑制活性，这相当于同时针对数千种天然蛋白质筛选文库。该概念验证研究将：1）证明优先考虑所研究目标的全面性超过合成化合物库的大小，可以对所观察到的药效团交叉反应性所涉及的分子特征进行独特而有效的理解。2）证明可以系统地处理药效团重新利用到迄今为止具有生物医学意义的非靶向蛋白质。3）创建一个互联网-基于可视化的工具，允许药物发现科学家探索和与这个前所未有的数据集互动，形成新的生物和化学假设。这一努力的成功将证明化学蛋白质组学可以提供急需的除了经典的基于靶点的（其中研究的靶点很少）和基于表型的（其中靶点去卷积通常是困难的）药物发现策略之外。我们预计，我们的药效团为中心的方法，先验充分表征药物分子与蛋白质组的相互作用，将提供数据集，可以事后挖掘特定的目标感兴趣。这在个性化医疗的出现需要针对非经典蛋白质的个性化药物时特别相关，因此通常是非靶向蛋白质。

It has become very clear that most therapeutic drugs modulate the function of more than one protein. Therefore, repurposing a drug for a new medical indication in light of its other targets has emerged as an opportunistic but successful concept. However, most of the time, such new activities are only identified after years of use because current drug discovery approaches never investigate the full potential of a particular drug or the underlying pharmacophore. Chemical proteomics has emerged as a prime approach to delineate the target spectrum of small molecules without an a priori hypothesis and we have developed efficient workflows to systematically unravel drug repurposing opportunities of clinically investigated drugs. In this new interdisciplinary research proposal we will combine medicinal chemistry, biochemistry, mass spectrometry and bioinformatics to establish a pharmacophore-centric approach to drug discovery that systematically investigates the target space of any given small molecule on a proteome-wide scale to establish its structure-affinity relationship (SAR). More specifically, we will measure and compare the target profiles of a small library of one hundred structurally related molecules based on the same chemical scaffold with known inhibitory activity for kinase- and bromodomains which is equivalent to screening the library against thousands of native proteins simultaneously. This proof-of-concept study will:1) Demonstrate that prioritizing the comprehensiveness of the investigated targets over the size of the library of synthesized compounds procures a unique and efficient understanding of the molecular features involved in the observed cross-reactivities of the pharmacophore.2) Demonstrate that pharmacophore repurposing to hitherto untargeted proteins of biomedical significance can be approached systematically.3) Create an internet-based visualization tool allowing drug discovery scientists to explore and interact with this unprecedented dataset to form new biological and chemical hypothesis.The success of this endeavour shall prove that chemical proteomics can provide a much needed addition to the classical target-based (in which very few targets are investigated) and phenotypic-based (where target deconvolution is often difficult) drug discovery strategies. We anticipate that our pharmacophore-centric approach, which a priori fully characterizes the drug molecule with respect to its interaction with the proteome will provide datasets that can a posteriori be mined for a particular target of interest. This is of particular relevance in times when the advent of personalised medicine will require personalised drugs against non-classical and therefore typically untargeted proteins.