dc.contributor.author | Firth, NC | |
dc.contributor.author | Atrash, B | |
dc.contributor.author | Brown, N | |
dc.contributor.author | Blagg, J | |
dc.date.accessioned | 2020-07-24T15:07:13Z | |
dc.date.issued | 2015-06-22 | |
dc.identifier.citation | Journal of chemical information and modeling, 2015, 55 (6), pp. 1169 - 1180 | |
dc.identifier.issn | 1549-9596 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3871 | |
dc.identifier.eissn | 1549-960X | |
dc.identifier.doi | 10.1021/acs.jcim.5b00073 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | 1169 - 1180 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER CHEMICAL SOC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Microsomes | |
dc.subject | Humans | |
dc.subject | Purines | |
dc.subject | Ligands | |
dc.subject | Drug Stability | |
dc.subject | Computational Biology | |
dc.subject | Oxidation-Reduction | |
dc.subject | Drug Design | |
dc.subject | Algorithms | |
dc.subject | Cyclin-Dependent Kinase 2 | |
dc.subject | Roscovitine | |
dc.title | MOARF, an Integrated Workflow for Multiobjective Optimization: Implementation, Synthesis, and Biological Evaluation. | |
dc.type | Journal Article | |
rioxxterms.versionofrecord | 10.1021/acs.jcim.5b00073 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2015-06-09 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Journal of chemical information and modeling | |
pubs.issue | 6 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 55 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Medicinal Chemistry 1 | |
dc.contributor.icrauthor | Firth, Nicholas | |