MOARF, an Integrated Workflow for Multiobjective Optimization: Implementation, Synthesis, and Biological Evaluation

We
describe the development and application of an integrated, multiobjective
optimization workflow (MOARF) for directed medicinal chemistry design.
This workflow couples a rule-based molecular fragmentation scheme
(SynDiR) with a pharmacophore fingerprint-based fragment replacement
algorithm (RATS) to broaden the scope of reconnection options considered
in the generation of potential solution structures. Solutions are
ranked by a multiobjective scoring algorithm comprising ligand-based
(shape similarity) biochemical activity predictions as well as physicochemical
property calculations. Application of this iterative workflow to optimization
of the CDK2 inhibitor Seliciclib (CYC202, R-roscovitine) generated
solution molecules in desired physicochemical property space. Synthesis
and experimental evaluation of optimal solution molecules demonstrates
CDK2 biochemical activity and improved human metabolic stability.