MOARF, an Integrated Workflow for Multiobjective Optimization: Implementation, Synthesis, and Biological Evaluation
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Firth, N. C., Atrash, B., Brown, N., Blagg, J.
(2015)
MOARF, an Integrated Workflow for Multiobjective Optimization: Implementation, Synthesis, and Biological Evaluation.
JOURNAL OF CHEMICAL INFORMATION AND MODELING, 55 (6).
pp. 1169-1180.
ISSN 1549-9596
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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.
| Item Type: | Article |
|---|---|
| Authors (ICR Faculty only): | Blagg, Julian |
| All Authors: | Firth, N. C., Atrash, B., Brown, N., Blagg, J. |
| Additional Information: | ISI Document Delivery No.: CL4DQ Times Cited: 0 Cited Reference Count: 57 Firth, Nicholas C. Atrash, Butrus Brown, Nathan Blagg, Julian Institute of Cancer Research; Cancer Research UK [C309/A8274] N.C.F. is funded by the Institute of Cancer Research, N.B. and J.B. are funded by Cancer Research UK Grant No. C309/A8274. N.C.F. would like to thank Kathy Boxall for her help with running the CDK2 assays, Angela Hayes and Jennie Roberts for performing the HLM assays, and Yi Mok for helpful comments on the manuscript. We thank Dr. Amin Mirza, Mr. Meirion Richards and Dr. Maggie Liu for their assistance with NMR, mass spectrometry and HPLC. Amer chemical soc Washington |
| Uncontrolled Keywords: | de-novo design drug design medicinal chemistry genetic algorithm inhibitors molecules fingerprints program docking library |
| Research teams: | ICR divisions > Cancer Therapeutics > Medicinal Chemistry 1 (including Analytical Chemistry and In Silico Chemistry) |
| Depositing User: | Alexander Smithson |
| Date Deposited: | 17 Jul 2015 13:00 |
| Last Modified: | 22 Jul 2015 10:18 |
| URI: | http://publications.icr.ac.uk/id/eprint/14248 |
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