MOARF, an Integrated Workflow for Multiobjective Optimization: Implementation, Synthesis, and Biological Evaluation.
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Publication Date
2015-06-09Author
Firth, NC
Atrash, B
Brown, N
Blagg, J
Type
Journal Article
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Show full item recordAbstract
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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Licenseref URL
http://creativecommons.org/licenses/by/4.0/Version of record
Subject
Microsomes
Humans
Purines
Ligands
Drug Stability
Computational Biology
Oxidation-Reduction
Drug Design
Algorithms
Cyclin-Dependent Kinase 2
Roscovitine
Research team
Medicinal Chemistry 1
Language
eng
License start date
2015-06-09
Citation
Journal of chemical information and modeling, 2015, 55 (6), pp. 1169 - 1180