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.
