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

很明显，大多数治疗药物调节的是不止一种蛋白质的功能。因此，考虑到一种药物的其他目标，将其重新用于新的医学适应症已成为一个机会主义但成功的概念。然而，大多数情况下，这种新的活动只有在使用多年后才被发现，因为目前的药物发现方法从未调查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在没有先验假设的情况下描绘小分子靶标光谱的主要方法，我们已经开发出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方案中，我们将结合药物化学、生物化学、质谱学和生物信息学来建立以药效团为中心的药物发现方法，在蛋白质组范围内系统地研究任何给定小分子的靶空间，以建立其结构-亲和力关系(SAR)。更具体地说，我们将测量和比较一个由100个结构相关分子组成的小文库的目标轮廓，该文库基于相同的化学支架，具有已知的对激酶和溴域的抑制活性，这相当于同时筛选针对数千种天然蛋白质的文库。这项概念验证研究将：1)将研究目标的全面性放在合成化合物库的大小之上，从而获得对所观察到的药效团交叉反应所涉及的分子特征的独特而有效的理解。2)证明可以系统地研究药效团对迄今具有生物医学意义的非靶向蛋白质的再利用。3)创建一个基于互联网的可视化工具，允许药物发现科学家探索并与这一前所未有的数据集进行交互，以形成新的生物和化学假说。这一努力的成功将证明，化学蛋白质组学可以为传统的基于靶标的(基于表型(目标去卷积往往很困难)和基于表型的药物发现策略。我们预计，我们以药效团为中心的方法，即先验地充分描述药物分子与蛋白质组的相互作用，将提供可以在以后为特定感兴趣的目标挖掘的数据集。当个性化药物的出现将需要针对非经典蛋白质的个性化药物，从而通常是非靶向蛋白质时，这一点尤其相关。

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.