The Logic of Chemical Optimization

During
multiparameter chemical optimization, molecular capabilities
increase as hits evolve into leads and development candidates. Like
retrosynthetic analysis, where target molecules are transformed into
structurally simplified starting materials, we introduce retro-optimization
analysis, transforming sophisticated development candidates into less
capable leads and hits. To retrospectively understand the logic of
optimization in discovery campaigns, we enumerated a matched molecular
pair network and compared the actual route of optimization taken to
alternative theoretical routes of optimization. We noted differences
in the network and properties of the lead molecule compared to those
of alternatives. We identified substructures of the evolving ligand,
named “optimizons,” and tracked their emphasis and discovery.
While we initially defined and illustrated these methods for a single
project, our expansion to three additional discovery projects and
three external data sets proved consistent. We retrospectively define
the logic of optimization at the project, molecular, and submolecular
levels to prospectively guide current and future optimization campaigns.