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MOARF, an Integrated Workflow for Multiobjective Optimization: Implementation, Synthesis, and Biological Evaluation
Nicholas C Firth1, Butrus Atrash1, Nathan Brown1
1Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, U.K.
Abstract:
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.
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