Discovery & Synthesis Chemputer: An intelligent universal system for automated chemical synthesis and discovery across different hardware and scales

项目摘要 在这个合作项目中，我们将开发一个用于化学反应自动化和执行的系统 用于合成已知和未知分子的一系列硬件和规模。这项工作将 利用我们实验室过去6年在化学计算机(可编程化学合成)上取得的进展 机器人)和化学原理(化学合成用一种化学物质表达的概念 代码可以可靠地在任何兼容的硬件上运行)。提出了三个具体目标：1.发展 将运行合成协议的化学编程语言标准；2.模块化插件的开发 以及用于化学合成的硬件，包括与第三方系统的接口；3.创建反应 化学合成和发现的筛选系统。这些目标将在五年内制定。 与NCATS以高度整合和协作的工作方式开展工作。在1-2年间，我们将致力于 通过制定规范、实施计划、原型、测试集成概念、 在此之后，将在3-5年内在NCATS进行部署、集成和测试。通过开发 一种用于化学合成的可操作的编程语言，可指定反应的要求 准确地说，我们将确保可编程化学，就像计算一样，能够在兼容的基础上变得普遍 硬件。我们将要开发的编程语言是基于我们的化学描述语言χDL(1.0)， 它是开源的。我们将引入更强大的函数，例如for循环和if When条件，以便 χDL(2.0)将等同于一种函数式计算机编程语言，而不是用于 计算，χDL(2.0)将用于化学操作。这一功能升级非常重要，因为 语言将变得更加可移植和普遍。这是因为语言不会依赖于 不适合化学自动化的外部语言。该系统将在格拉斯哥和NCATS进行验证 使用一系列覆盖有机化学的知名反应，并将涉及几个案例 展示新发现的化学如何被编码的研究。我们还将探索一系列 液-液和固-液萃取体系的合成规模和新方法 用于纯化和图书馆开发的膜技术。该系统将用于优化现有的 化学反应和靶标，以及使用机器学习系统探索新靶标。模块化的 分析软件系统-布里奇将包括核磁共振、IR、MS和高效液相色谱分析，以提供实时反馈。该项目 结果将是作为起点的新化学实体的识别、设计、合成和验证 用于药物开发的新靶点，以及扩大可用于药物筛选的化学空间。这个 项目将在NCATS和格拉斯哥担任领导，团队将与管理层联合协调 每月正式开会的团队，每周和每两周定期开会，每季度举行一次 评论。一个指导委员会将审查进展并向团队提供建议。

Project Summary In this collaborative project we will develop a system for the automation and execution of chemical reactions across a range of hardware and scales for the synthesis of known and unknown molecules. This work will leverage the last 6 years of progress in our laboratory on the Chemputer (a programmable chemical synthesis robot) and the principle of Chemputation (the concept that a chemical synthesis expressed in a type of chemical code can be run on any compatible hardware reliably). Three specific aims are proposed: 1. To develop the chemical programming language standard that will run the synthesis protocols; 2. Development of modular plug and play hardware for chemical synthesis including interfaces to 3rd party systems; 3. Creation of a reaction screening system for chemical synthesis and discovery. These aims will be developed over the five-year period in a highly integrated and collaborative working modus operandi with NCATS. During years 1-2 we will work on all three Specific Aims by developing specifications, implementation plans, prototypes, test integration concepts, and this will be followed by, in years 3-5, cycles of deployment, integration, and testing at NCATS. By developing an operational programming language for chemical synthesis that can specify the requirements for the reactions precisely, we will ensure that programmable chemistry, like computation, can become universal on compatible hardware. The programming language we will develop is based on our chemical description language, χDL (1.0), which is open source. We will introduce more powerful functions e.g., for loops and if when conditions so that χDL (2.0) will be equivalent to a functional computer programming language, but rather than being used for computation, χDL (2.0) will be for chemical operations. This upgrade in functionality is important since the language will become more portable and universal. This is because the language will not be dependent upon external languages not suitable for chemistry automation. This system will be validated at Glasgow and NCATS using a range of well-known reactions covering the span of organic chemistry and will involve several case studies demonstrating how newly discovered chemistry can be encoded. We will also explore a range of synthesis scales and new approaches to liquid-liquid and solid-liquid extraction systems using state of the art membrane technologies for purification and library development. The system will be used to optimise existing chemical reactions and targets as well as explore for new targets using a machine learning system. A modular analytics software system-bridge will include NMR, IR, MS, and HPLC to provide real-time feedback. The project outcomes will be the identification, design, synthesis, and validation of new chemical entities as starting points for drug development of novel targets, and the expansion of chemical space available for drug screening. The project will have a lead at NCATS and Glasgow, and the teams will be jointly coordinated with a management team that will be meeting formally every month, with frequent weekly and bi-weekly meetings, and quarterly reviews. A steering committee will review progress and give advice to the teams.