Unusual Pharmacophores and New Tools for Cross-Coupling

不寻常的药效团和交叉偶联的新工具

基本信息

批准号：
10578847
负责人：
Ryan Ashok Shenvi
金额：
$ 69.29万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2027-03-31
项目状态：
未结题

项目摘要

Abstract Bioassay-guided fractionation of cells uncovers small molecules that bind receptors in new and unexpected ways. These cellular metabolites emerge from evolution with complex molecular features preoptimized for function. High stereochemical content, high globularity and diverse heteroatom content impart greater specificity of protein binding and greater aqueous solubility than simple, flat and non-polar substances. Parametrization of large molecular libraries have supported a correlation between evolutionary optimization and therapeutic design: “drug” chemical space is optimized away from commercial building blocks and towards natural products (NP space). These types of molecules represent a challenge to chemical synthesis, however, and require the development of new chemical tools for optimization and human use. This grant advances our work towards the rapid access and navigation of NP space. Our robust routes to complex molecules have proven practical: synthesis allowed us to annotate and modify biological function. Over the coming grant period we extend this approach into three areas. First, we develop the chemistry to access two chemotypes with known phenotypic effects but unknown biological targets. One target has stimulated the discovery of a new, stereoselective cross-coupling reaction, whereas another has inspired the conversion of inert scaffolds to new warheads for protein adduction. Second, we describe rapid access to complex ligands of known biological targets that embody ‘combinatorial’ aggregates of multiple proteins. Diverse structural modifications of the complex small molecule will enable a search for selectivity among these combinatorial targets with consequences for therapeutic development. Third, selectivity defines the future goals of dual-catalytic cross-couplings to reach NP space: we seek to address substrate selectivity, relative stereoselectivity and absolute stereoselectivity.

抽象的细胞的生物测定引导分馏发现在新的和意外的受体结合的小分子方式。这些细胞代谢产物从进化中浮现，复杂的分子特征先前功能。高立体化学含量，高球形和潜水杂原子含量更大蛋白质结合的特异性和更大的水溶性比简单，扁平和非极性物质的特异性。大分子库的参数化支持了进化优化之间的相关性和热设计：“药物”化学空间已优化，远离商业构建块，朝向天然产品（NP空间）。但是，这些类型的分子代表了化学合成的挑战并需要开发新的化学工具以优化和人类使用。这笔赠款将我们的工作促进了NP空间的快速访问和导航。我们强大的路线复杂的分子已被证明是实用的：合成使我们能够注释并修改生物学功能。在接下来的赠款期内，我们将此方法扩展到三个领域。首先，我们将化学反应发展为访问两种具有已知表型效应但未知生物学靶标的化学型。一个目标有刺激了新的立体选择性交叉耦合反应的发现，而另一个则启发了将惰性脚手架转换为添加蛋白质的新弹头。第二，我们描述了快速进入体现多种蛋白质“组合”聚集体的已知生物学靶标的复杂配体。复杂小分子的各种结构修饰将使它们之间的选择性搜索组合目标与热发育的后果。第三，选择性定义了未来双催化交叉耦合到达NP空间的目标：我们试图解决底物选择性，相对立体选择性和绝对立体选择性。