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dc.contributor.authorMok, NYen_US
dc.contributor.authorBrown, Nen_US
dc.coverage.spatialUnited Statesen_US
dc.date.accessioned2017-03-06T15:23:08Z
dc.date.issued2017-01-23en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/27990817en_US
dc.identifier.citationJ Chem Inf Model, 2017, 57 (1), pp. 27 - 35en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/471
dc.identifier.eissn1549-960Xen_US
dc.identifier.doi10.1021/acs.jcim.6b00386en_US
dc.description.abstractEstablishing structure-activity relationships (SARs) in hit identification during early stage drug discovery is important in accelerating hit confirmation and expansion. We describe the development of EnCore, a systematic molecular scaffold enumeration protocol using single atom mutations, to enhance the application of objective scaffold definitions and to enrich SAR information from analysis of high-throughput screening output. A list of 43 literature medicinal chemistry compound series, each containing a minimum of 100 compounds, published in the Journal of Medicinal Chemistry was collated to validate the protocol. Analysis using the top representative Level 1 scaffolds this list of literature compound series demonstrated that EnCore could mimic the scaffold exploration conducted when establishing SAR. When EnCore was applied to analyze an HTS library containing over 200 000 compounds, we observed that over 70% of the molecular scaffolds matched extant scaffolds within the library after enumeration. In particular, over 60% of the singleton scaffolds with only one representative compound were found to have structurally related compounds after enumeration. These results illustrate the potential of EnCore to enrich SAR information. A case study using literature cyclooxygenase-2 inhibitors further demonstrates the advantage of EnCore application in establishing SAR from structurally related scaffolds. EnCore complements literature enumeration methods in enabling changes to the physicochemical properties of molecular scaffolds and structural modifications to aliphatic rings and linkers. The enumerated scaffold clusters generated would constitute a comprehensive collection of scaffolds for scaffold morphing and hopping.en_US
dc.format.extent27 - 35en_US
dc.languageengen_US
dc.language.isoengen_US
dc.subjectCyclooxygenase 2 Inhibitorsen_US
dc.subjectDrug Designen_US
dc.subjectDrug Evaluation, Preclinicalen_US
dc.subjectStructure-Activity Relationshipen_US
dc.titleApplications of Systematic Molecular Scaffold Enumeration to Enrich Structure-Activity Relationship Information.en_US
dc.typeJournal Article
rioxxterms.versionofrecord10.1021/acs.jcim.6b00386en_US
rioxxterms.licenseref.startdate2017-01-23en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfJ Chem Inf Modelen_US
pubs.issue1en_US
pubs.notesNo embargoen_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 (including Analytical Chemistry and In Silico Chemistry)
pubs.publication-statusPublisheden_US
pubs.volume57en_US
pubs.embargo.termsNo embargoen_US
icr.researchteamMedicinal Chemistry 1 (including Analytical Chemistry and In Silico Chemistry)en_US
dc.contributor.icrauthorBrown, Nathanen_US
dc.contributor.icrauthorMok, Ngaien_US


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