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dc.contributor.authorFirth, NCen_US
dc.contributor.authorAtrash, Ben_US
dc.contributor.authorBrown, Nen_US
dc.contributor.authorBlagg, Jen_US
dc.date.accessioned2020-07-24T15:07:13Z
dc.date.issued2015-06-09en_US
dc.identifier.citationJournal of chemical information and modeling, 2015, 55 (6), pp. 1169 - 1180en_US
dc.identifier.issn1549-9596en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3871
dc.identifier.eissn1549-960Xen_US
dc.identifier.doi10.1021/acs.jcim.5b00073en_US
dc.description.abstractWe 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.en_US
dc.formatPrint-Electronicen_US
dc.format.extent1169 - 1180en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectMicrosomesen_US
dc.subjectHumansen_US
dc.subjectPurinesen_US
dc.subjectLigandsen_US
dc.subjectDrug Stabilityen_US
dc.subjectComputational Biologyen_US
dc.subjectOxidation-Reductionen_US
dc.subjectDrug Designen_US
dc.subjectAlgorithmsen_US
dc.subjectCyclin-Dependent Kinase 2en_US
dc.titleMOARF, an Integrated Workflow for Multiobjective Optimization: Implementation, Synthesis, and Biological Evaluation.en_US
dc.typeJournal Article
rioxxterms.versionofrecord10.1021/acs.jcim.5b00073en_US
rioxxterms.licenseref.startdate2015-06-09en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfJournal of chemical information and modelingen_US
pubs.issue6en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 1
pubs.publication-statusPublisheden_US
pubs.volume55en_US
pubs.embargo.termsNot knownen_US
icr.researchteamMedicinal Chemistry 1en_US
dc.contributor.icrauthorBrown, Nathanen_US
dc.contributor.icrauthorBlagg, Julianen_US
dc.contributor.icrauthorFirth, Nicholasen_US


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Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/