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