Unusual Pharmacophores and New Tools for Cross-Coupling

不寻常的药效团和交叉偶联的新工具

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10578847
• 关键词: Address; Area; Binding Proteins; Biological; Biological Assay; Biological Process; Cell Fractionation; Chemicals; Chemistry; Complex; Coupling; Development; Evolution; Foundations; Future; Goals; Grant; Human; Ligands; Modification; Molecular; Molecular Bank; Natural Products; Pharmaceutical Preparations; Phenotype; Proteins; Reaction; Route; Solubility; Specificity; Therapeutic; Work; adduct; aqueous; chemical synthesis; combinatorial; design; human disease; invention; neuroregulation; novel therapeutics; pharmacophore; receptor binding; scaffold; secondary metabolite; small molecule; therapeutic development; tool

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.

摘要 生物测定引导的细胞分级分离揭示了新的和意想不到的结合受体的小分子 的方式这些细胞代谢物从进化中出现，具有预先优化的复杂分子特征， 功能高的立体化学含量、高的球形度和不同的杂原子含量赋予更大的 蛋白质结合的特异性和比简单的、扁平的和非极性物质更大的水溶性。 大型分子库的参数化支持进化优化之间的相关性 和治疗设计：“药物”化学空间被优化，远离商业建筑模块， 自然产物（NP空间）。然而，这些类型的分子对化学合成提出了挑战， 并需要开发新的化学工具以优化和人类使用。 这笔赠款推进了我们对NP空间的快速访问和导航的工作。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和修改生物功能。 在接下来的赠款期间，我们将这种方法扩展到三个领域。首先，我们发展化学， 获得两种具有已知表型效应但未知生物靶点的化学型。一个目标有 刺激了一个新的，立体选择性交叉偶联反应的发现，而另一个启发了 将惰性支架转化为用于蛋白加合的新弹头。其次，我们描述了快速访问 已知生物靶标的复合配体，其体现了多种蛋白质的“组合”聚集体。 复杂小分子的不同结构修饰将使得能够在这些小分子中寻找选择性。 组合靶点对治疗开发的影响。第三，选择性定义未来 双催化交叉耦合的目标，以达到NP空间：我们寻求解决底物的选择性，相对 立体选择性和绝对立体选择性。