title: MOARF, an Integrated Workflow for Multiobjective Optimization: Implementation, Synthesis, and Biological Evaluation.
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.
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, U.K.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Firth
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, U.K.
authors.forename: Butrus
authors.initials: B
authors.lastname: Atrash
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, U.K.
authors.forename: Nathan
authors.initials: N
authors.lastname: Brown
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, U.K.
authors.forename: Julian
authors.initials: J
authors.lastname: Blagg
mesh_terms: D000465:Algorithms; D019295:Computational Biology / Q000379:methods*; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors; D015195:Drug Design; D004355:Drug Stability; D006801:Humans; D008024:Ligands; D008861:Microsomes / Q000378:metabolism; D010084:Oxidation-Reduction; D011687:Purines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000077546:Roscovitine
chemical_list: D008024:Ligands; D011687:Purines; D000077546:Roscovitine; D051357:Cyclin-Dependent Kinase 2