Vectorial Cores for Fragment-based Drug-Discovery

用于基于片段的药物发现的矢量核心

• 批准号: 2571878
• 金额: --
• 依托单位: Durham University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2571878
• 关键词: Vectorial; Cores; Fragment; based; Drug

This project will develop new synthetic methodology to enable the construction of a toolbox of vectorially functionalized, previously unsynthesised heterocyclic scaffolds for fragment-based drug design (FBDD). Whilst FBDD has been successfully applied to a number of studies this has been achieved using a relatively limited set of heteroaromatic scaffolds. Although, considerable recent effort has been directed towards the development of 3D cores, comparatively little effort has been expended to increase the diversity of heterocyclic fragments often used as auxiliary decoration for these 3D-interiors. Reflecting this, studies have shown that whilst theoretical chemotherapeutic space is diverse in terms of structure and physico-chemical properties, most heterocyclic structures are located in small islands of structural similarity with medicinal chemists being unable to explore unoccupied and therefore unprecedented regions. In this project we propose build on these analyses and prepare previously undescribed heterocyclic systems. A challenge in using such molecules for FBDD is functionalising heterocyclic fragments to enable desired connections to be established with alternative substituents requiring de novo and often challenging synthesis. Consequently, an important aspect of the proposed project will be to develop generic complementary methods for late stage functionalisation of each heterocycle that can be applied in a sequential and vectorially diverse manner. In particular ,complexity will be introduced through borylation, fluorination and metalation to provide orthogonal vectors for points of combination and handles to ensure suitable physicochemical profiles can be incorporated into each structure. To validate the new fragment library all compounds will be assayed for target engagement in ongoing chemical biology studies in Durham and elsewhere.

该项目将开发新的合成方法学，以构建用于基于片段的药物设计(FBDD)的矢量功能化、先前未合成的杂环支架的工具箱。虽然FBDD已经成功地应用于一些研究，但这是使用相对有限的杂芳族支架实现的。尽管最近针对3D核心的开发已经做出了相当大的努力，但在增加通常用作这些3D内部的辅助装饰的杂环片段的多样性方面花费的努力相对较少。考虑到这一点，研究表明，尽管理论上的化疗空间在结构和物理化学性质方面是不同的，但大多数杂环结构位于结构相似的小岛上，药物化学家无法探索空置的区域，因此是前所未有的。在这个项目中，我们建议建立在这些分析的基础上，并制备以前未描述的杂环系统。将这种分子用于FBDD的一个挑战是将杂环片段功能化，使其能够与需要从头开始并经常具有挑战性的合成的替代取代基建立所需的连接。因此，拟议项目的一个重要方面将是为每个杂环的后期官能化开发通用的补充方法，这些方法可以以顺序和矢量多样化的方式应用。特别是，将通过硼化、氟化和金属化引入复杂性，为结合点和手柄提供正交向量，以确保每个结构中都可以结合合适的物理化学特征。为了验证新的片段文库，将在达勒姆和其他地方进行正在进行的化学生物学研究，对所有化合物进行目标参与测试。