MOARF, an Integrated Workflow for Multiobjective Optimization: Implementation, Synthesis, and Biological Evaluation.

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acs.jcim.5b00073.pdf (1.2 MB)

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ICR Authors

Firth, Nicholas

Authors

Firth, NC
Atrash, B
Brown, N
Blagg, J

Document Type

Journal Article

Date

2015-06-22

Date Accepted

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.

Citation

Journal of chemical information and modeling, 2015, 55 (6), pp. 1169 - 1180

DOI

10.1021/acs.jcim.5b00073

URI

https://repository.icr.ac.uk/handle/internal/3871

Rights

https://creativecommons.org/licenses/by/4.0

Source Title

Publisher

AMER CHEMICAL SOC

ISSN

1549-9596

eISSN

1549-960X

Collections

Cancer Therapeutics

Research Team

Medicinal Chemistry 1

Notes