Diversity Oriented Synthesis of Complex Small Molecules

现代小分子医学的基础是发现一些分子，这些分子使科学家能够通过抑制或激活感兴趣的蛋白质来询问蛋白质的功能，这通常会导致新的治疗策略和药物。发现新的小分子药物的一种重要的现代方法是基于片段的药物发现（FBDD），其中小分子（“片段”）在基于结构的筛选中针对感兴趣的蛋白质靶标进行评估，以确定与蛋白质靶标结合的实体。这些信息被用于构建高强度的化学探针或治疗分子，通过对初始片段撞击的合成操作，从初始的弱结合片段中提取。虽然这是一种强大的方法，但片段文库的结构多样性仍然有限，往往缺乏与改进的发现成功相对应的重要特征，包括支架多样性（不同环系统的数量）sp3碳的分数和三维形状。最近的一份报告指出，缺乏合成的“出口载体”，即片段可以衍生的官能团，是发现过程中的一个重大瓶颈。同一份报告呼吁重新努力合成解决这些问题的新片段。这个博士项目将以多样性为导向的综合来解决这些问题。

The basis of modern small molecule medicine is the discovery of molecules which allow scientists to interrogate protein function by inhibition or activation of the protein of interest, often leading to new therapeutic strategies and medicines. One important modern approach to the discovery of new small molecule medicines is fragment-based drug discovery (FBDD), in which small molecules ("fragments") are evaluated in structure-based screens against protein targets of interest in order to identify entities which bind to the protein target. This information is used to build highly potent chemical probes or therapeutic molecules from initial, weakly binding fragments via synthetic manipulation of the initial fragment hit. Although this is a powerful approach, fragment libraries are still limited in their structural diversity, often lacking important features which correspond to improved discovery success, including scaffold diversity (number of different ring systems) fraction of sp3 carbons, and three-dimensional shape. One recent report has identified the lack of synthetic "exit vectors," or functional groups by which the fragments can be derivatised, as a significant bottleneck in the discovery process. vThis same report issued a call for renewed efforts into synthesis of novel fragments which address these issues. This PhD project will address these issues with diversity-oriented synthesis.