MOARF, an Integrated Workflow for Multiobjective Optimization: Implementation, Synthesis, and Biological Evaluation.
View/ Open
Date
2015-06-22ICR Author
Author
Firth, NC
Atrash, B
Brown, N
Blagg, J
Type
Journal Article
Metadata
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.
Collections
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
Publisher
AMER CHEMICAL SOC