Informatics and Machine Learning Modules for Research Planning, Scheduling, Simulation, and Optimization in the ASPIRE Autonomous Laboratory

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PROJECT SUMMARY Access to complex chemical matter (e.g., small molecule drug candidates) is a core requirement for testing biological hypotheses and probing human health. Current approaches to chemical synthesis rely on time-consuming planning and labor-intensive manual synthesis, which is a rate-limiting step in the discovery of new functional molecules. This collaborative project comprises the development of several virtual modules to support the multi-step chemical synthesis of new molecules in autonomous laboratories. These modules are designed to benefit traditional synthetic chemists in addition to automation chemists using the integrated hardware platform being developed by the ASPIRE team at NCATS. Computer-aided synthesis planning can be viewed as a hierarchical process of elaboration starting from the list of molecules of interest: (1) retrosynthetic planning to identify suitable starting materials and intermediates, (2) reaction condition recommendation to identify the conditions with which each reaction step should be run, (3) translation of hypothetical reaction steps into action sequences executable on automated hardware. Optional but valuable components include (4) recording procedures through an experimental planning module, (5) optimization of the timing and order of action sequences to most efficiently synthesize multiple synthetic targets via a digital twin of the platform, and (6) the iterative optimization of process parameters based on experimental responses in a feedback loop. This program will address each of these needs through the development of new software solutions employing state of the art algorithms in graph network theory, cheminformatics, deep learning for chemistry, and optimization. Software modules will be written using established software development best practices for ease of cross-platform deployment (via containerization) and long-term maintainability (via extensive documentation). Further, each module will be deployed as an independent microservice with a common application programming interface (API) format for inter-module communication and integration with existing NCATS modules, including graphical user interfaces. These efforts will be accomplished through close partnership between MIT and NCATS to enhance the overall capabilities of the NCATS ASPIRE platform.