dc.contributor.author | Liu, M | |
dc.contributor.author | Mirza, A | |
dc.contributor.author | McAndrew, PC | |
dc.contributor.author | Thapaliya, A | |
dc.contributor.author | Pierrat, OA | |
dc.contributor.author | Stubbs, M | |
dc.contributor.author | Hahner, T | |
dc.contributor.author | Chessum, NEA | |
dc.contributor.author | Innocenti, P | |
dc.contributor.author | Caldwell, J | |
dc.contributor.author | Cheeseman, MD | |
dc.contributor.author | Bellenie, BR | |
dc.contributor.author | van Montfort, RLM | |
dc.contributor.author | Newton, GK | |
dc.contributor.author | Burke, R | |
dc.contributor.author | Collins, I | |
dc.contributor.author | Hoelder, S | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2024-02-06T13:29:32Z | |
dc.date.available | 2024-02-06T13:29:32Z | |
dc.date.issued | 2023-08-10 | |
dc.identifier.citation | Journal of Medicinal Chemistry, 2023, 66 (15), pp. 10617 - 10627 | en_US |
dc.identifier.issn | 0022-2623 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/6154 | |
dc.identifier.eissn | 1520-4804 | |
dc.identifier.eissn | 1520-4804 | |
dc.identifier.doi | 10.1021/acs.jmedchem.3c00758 | |
dc.identifier.doi | 10.1021/acs.jmedchem.3c00758 | |
dc.description.abstract | High hit rates from initial ligand-observed NMR screening can make it challenging to prioritize which hits to follow up, especially in cases where there are no available crystal structures of these hits bound to the target proteins or other strategies to provide affinity ranking. Here, we report a reproducible, accurate, and versatile quantitative ligand-observed NMR assay, which can determine Kd values of fragments in the affinity range of low μM to low mM using transverse relaxation rate R2 as the observable parameter. In this study, we examined the theory and proposed a mathematical formulation to obtain Kd values using non-linear regression analysis. We designed an assay format with automated sample preparation and simplified data analysis. Using tool compounds, we explored the assay reproducibility, accuracy, and detection limits. Finally, we used this assay to triage fragment hits, yielded from fragment screening against the CRBN/DDB1 complex. | |
dc.format | Print-Electronic | |
dc.format.extent | 10617 - 10627 | |
dc.language | eng | |
dc.language.iso | eng | en_US |
dc.publisher | AMER CHEMICAL SOC | en_US |
dc.relation.ispartof | Journal of Medicinal Chemistry | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | Ligands | |
dc.subject | Reproducibility of Results | |
dc.subject | Proton Magnetic Resonance Spectroscopy | |
dc.subject | Small Molecule Libraries | |
dc.subject | Drug Discovery | |
dc.subject | Protein Binding | |
dc.title | Determination of Ligand-Binding Affinity (Kd) Using Transverse Relaxation Rate (R2) in the Ligand-Observed 1H NMR Experiment and Applications to Fragment-Based Drug Discovery. | en_US |
dc.type | Journal Article | |
dcterms.dateAccepted | 2023-07-19 | |
dc.date.updated | 2024-02-06T12:03:05Z | |
rioxxterms.version | VoR | en_US |
rioxxterms.versionofrecord | 10.1021/acs.jmedchem.3c00758 | en_US |
rioxxterms.licenseref.startdate | 2023-08-10 | |
rioxxterms.type | Journal Article/Review | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/37467168 | |
pubs.issue | 15 | |
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/Hit Discovery & Structural Design | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 3 | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 4 (including Analytical Chemistry) | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Structural Biology | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design | |
pubs.publication-status | Published | |
pubs.publisher-url | http://dx.doi.org/10.1021/acs.jmedchem.3c00758 | |
pubs.volume | 66 | |
icr.researchteam | Hit Discov Struct Design | en_US |
icr.researchteam | Medicinal Chemistry 4 | en_US |
icr.researchteam | Medicinal Chemistry 3 | en_US |
dc.contributor.icrauthor | Pierrat, Olivier | |
dc.contributor.icrauthor | Caldwell, John | |
dc.contributor.icrauthor | Cheeseman, Matthew | |
dc.contributor.icrauthor | Van Montfort, Robert | |
dc.contributor.icrauthor | Newton, Gary | |
dc.contributor.icrauthor | Burke, Rosemary | |
icr.provenance | Deposited by Dr Olivier Pierrat on 2024-02-06. Deposit type is initial. No. of files: 1. Files: Determination of Ligand-Binding Affinity (iKisubdsub) Using Transverse Relaxation Rate (iRisub2sub) in the Ligand-Observed s.pdf | |