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及生物化学研究领域。基于碎片的药物发现包括识别与感兴趣的生物目标弱结合的小化合物，并将这些片段结合到更大的分子中，目的是产生一个更强结合目标的实体。片段的复杂性有助于提高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。异构性--限制分子键的旋转--是一种可以有效增加化合物几何复杂性的现象，特别是当键旋转所需的能量(旋转障碍)很高时。我们的目标是寻找与激酶蛋白强烈和选择性结合的阿托异构体探针化合物。该项目将涉及开发合成阿托异构体化合物的新方法，并将产生具有高选择性旋转障碍的新的医学相关片段。随后，将评估它们的旋转障碍以及它们对各种蛋白质靶标(包括激酶)的生物活性。蛋白质浸泡和X射线衍射结晶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，设计的探针可能在肿瘤学和炎症领域有用。

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.