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dc.contributor.authorFirth, NC
dc.contributor.authorAtrash, B
dc.contributor.authorBrown, N
dc.contributor.authorBlagg, J
dc.date.accessioned2020-07-24T15:07:13Z
dc.date.issued2015-06-09
dc.identifier.citationJournal of chemical information and modeling, 2015, 55 (6), pp. 1169 - 1180
dc.identifier.issn1549-9596
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3871
dc.identifier.eissn1549-960X
dc.identifier.doi10.1021/acs.jcim.5b00073
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.
dc.formatPrint-Electronic
dc.format.extent1169 - 1180
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectMicrosomes
dc.subjectHumans
dc.subjectPurines
dc.subjectLigands
dc.subjectDrug Stability
dc.subjectComputational Biology
dc.subjectOxidation-Reduction
dc.subjectDrug Design
dc.subjectAlgorithms
dc.subjectCyclin-Dependent Kinase 2
dc.subjectRoscovitine
dc.titleMOARF, an Integrated Workflow for Multiobjective Optimization: Implementation, Synthesis, and Biological Evaluation.
dc.typeJournal Article
rioxxterms.versionofrecord10.1021/acs.jcim.5b00073
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2015-06-09
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfJournal of chemical information and modeling
pubs.issue6
pubs.notesNot known
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.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-statusPublished
pubs.volume55
pubs.embargo.termsNot known
icr.researchteamMedicinal Chemistry 1en_US
dc.contributor.icrauthorBrown, Nathanen
dc.contributor.icrauthorBlagg, Julianen
dc.contributor.icrauthorFirth, Nicholasen


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