Direct Optimization across Computer-Generated Reaction Networks Balances Materials Use and Feasibility of Synthesis Plans for Molecule Libraries

The
synthesis of thousands of candidate compounds in drug discovery
and development offers opportunities for computer-aided synthesis
planning to simplify the synthesis of molecule libraries by leveraging
common starting materials and reaction conditions. We develop an optimization-based
method to analyze large organic chemical reaction networks and design
overlapping synthesis plans for entire molecule libraries so as to
minimize the overall number of unique chemical compounds needed as
either starting materials or reaction conditions. We consider multiple
objectives, including the number of starting materials, the number
of catalysts/solvents/reagents, and the likelihood of success of the
overall syntheses plan, to select an optimal reaction network to access
the target molecules. The library synthesis planning task was formulated
as a network flow optimization problem, and we design an efficient
decomposition scheme that reduces solution time by a factor of 5 and
scales to instance with 48 target molecules and nearly 8000 intermediate
reactions within hours. In four case studies of pharmaceutical compounds,
the approach reduces the number of starting materials and catalysts/solvents/reagents
needed by 32.2 and 66.0% on average and up to 63.2 and 80.0% in the
best cases. The code implementation can be found at https://github.com/Coughy1991/Molecule_library_synthesis.