Atropisomeric Fragments in Drug Discovery and Probe Compound Development

该项目属于EPSRC合成有机化学和化学生物学与生物化学研究领域。基于片段的药物发现包括识别与感兴趣的生物靶标结合较弱的小化合物，并将这些片段合并到更大的分子中，以产生与靶标结合更强的实体。片段的复杂性可以帮助增加它所结合的分子的活性和选择性，这在药物发现过程中是有价值的。旋回异构是一种限制分子键旋转的现象，它可以有效地增加化合物的几何复杂性，特别是当键旋转所需的能量（“旋转势垒”）很高时。我们的目的是鉴定atropisomer探针化合物，强结合和选择性激酶蛋白。该项目将涉及开发合成atrosomomer化合物的新方法，并将以选择性方式产生具有高旋转屏障的新的药用相关片段。随后将评估它们的旋转屏障及其对各种蛋白质靶标（包括激酶）的生物活性。蛋白质浸泡和x射线衍射晶体学等方法将有助于确定这些化合物与目标蛋白质的相互作用。如果成功，设计的探针可以用于肿瘤和炎症领域。

This project falls within the EPSRC Synthetic Organic Chemistry and Chemical Biology & Biological Chemistry research areas.Fragment-based drug discovery consists of identifying small chemical compounds that weakly bind to a biological target of interest and incorporating these fragments into a larger molecule with the intent of generating an entity that binds the target more strongly. The complexity of a fragment can help to increase the activity and the selectivity of the molecule it is incorporated into, which is valuable in the drug discovery process. Atropisomerism - restricted rotation about a molecular bond - is a phenomenon that can effectively increase the geometrical complexity of a compound, especially when the energy necessary for the bond to rotate (the 'barrier to rotation') is high.We aim to identify atropisomeric probe compounds that bind strongly and selectively to kinase proteins. The project will involve the development of new methods for the synthesis of atropisomeric compounds and will generate new medicinally relevant fragments with a high barrier to rotation in a selective fashion. Subsequently their barrier to rotation and their biological activity towards various protein targets (including kinases) will be assessed. Methods such as protein soaking and X-ray diffraction crystallography will be useful to determine the interactions of such compounds with target proteins. If successful, the designed probes could be useful in the fields of oncology and inflammation.