[NMR paper] 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
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
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 K(d) values of fragments...
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07-20-2023 06:33 AM
[NMR paper] (19)F NMR viewed through two different lenses: ligand-observed and protein-observed (19)F NMR applications for fragment-based drug discovery
(19)F NMR viewed through two different lenses: ligand-observed and protein-observed (19)F NMR applications for fragment-based drug discovery
^(19)F NMR has emerged as a powerful tool in drug discovery, particularly in fragment-based screens. The favorable magnetic resonance properties of the fluorine-19 nucleus, the general absence of fluorine in biological settings, and its ready incorporation into both small molecules and biopolymers, has enabled multiple applications of ^(19)F NMR using labeled small molecules and proteins in biophysical, biochemical, and cellular experiments. This...
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10-27-2021 10:50 PM
[NMR paper] NMR spectroscopy of the main protease of SARS-CoV-2 and fragment-based screening identify three protein hotspots and an antiviral fragment
NMR spectroscopy of the main protease of SARS-CoV-2 and fragment-based screening identify three protein hotspots and an antiviral fragment
The main protease (3CLp) of the SARS-CoV-2, the causative agent for the COVID-19 pandemic, is one of the main targets for drug development. To be active, 3CLp relies on a complex interplay between dimerization, active site flexibility, and allosteric regulation. The deciphering of these mechanisms is a crucial step to enable the search for inhibitors. In this context, using NMR spectroscopy, we studied the conformation of dimeric 3CLp from the...
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09-29-2021 12:23 PM
[NMR paper] Paramagnetic relaxation enhancement for protein-observed (19)F NMR as an enabling approach for efficient fragment screening.
Paramagnetic relaxation enhancement for protein-observed (19)F NMR as an enabling approach for efficient fragment screening.
Related Articles Paramagnetic relaxation enhancement for protein-observed (19)F NMR as an enabling approach for efficient fragment screening.
RSC Adv. 2016;6(98):95715-95721
Authors: Hawk LML, Gee CT, Urick AK, Hu H, Pomerantz WCK
Abstract
Protein-observed (19)F (PrOF) NMR is an emerging tool for ligand discovery. To optimize the efficiency of PrOF NMR experiments, paramagnetic relaxation enhancement...
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05-14-2017 12:16 PM
[NMR paper] Protein-observed (19)F-NMR for fragment screening, affinity quantification and druggability assessment.
Protein-observed (19)F-NMR for fragment screening, affinity quantification and druggability assessment.
Protein-observed (19)F-NMR for fragment screening, affinity quantification and druggability assessment.
Nat Protoc. 2016 Aug;11(8):1414-27
Authors: Gee CT, Arntson KE, Urick AK, Mishra NK, Hawk LM, Wisniewski AJ, Pomerantz WC
Abstract
NMR spectroscopy can be used to quantify the binding affinity between proteins and low-complexity molecules, termed 'fragments'; this versatile screening approach allows researchers to assess the...
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07-16-2016 04:54 AM
[NMR paper] Fragment Screening and Druggability Assessment for the CBP/p300 KIX Domain through Protein-Observed (19) F NMR Spectroscopy.
Fragment Screening and Druggability Assessment for the CBP/p300 KIX Domain through Protein-Observed (19) F NMR Spectroscopy.
Fragment Screening and Druggability Assessment for the CBP/p300 KIX Domain through Protein-Observed (19) F NMR Spectroscopy.
Angew Chem Int Ed Engl. 2015 Feb 4;
Authors: Gee CT, Koleski EJ, Pomerantz WC
Abstract
(19) F NMR spectroscopy of labeled proteins is a sensitive method for characterizing structure, conformational dynamics, higher-order assembly, and ligand binding. Fluorination of aromatic side...
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02-05-2015 12:00 PM
[NMR paper] Is NMR Fragment Screening Fine-Tuned to Assess Druggability of Protein-Protein Interactions?
Is NMR Fragment Screening Fine-Tuned to Assess Druggability of Protein-Protein Interactions?
Is NMR Fragment Screening Fine-Tuned to Assess Druggability of Protein-Protein Interactions?
ACS Med Chem Lett. 2014 Jan 9;5(1):23-28
Authors: Dias DM, Van Molle I, Baud MG, Galdeano C, Geraldes CF, Ciulli A
Abstract
Modulation of protein-protein interactions (PPIs) with small molecules has been hampered by a lack of lucid methods capable of reliably identifying high-quality hits. In fragment screening, the low ligand efficiencies associated with...
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01-18-2014 11:31 AM
[NMR paper] Druggability indices for protein targets derived from NMR-based screening data.
Druggability indices for protein targets derived from NMR-based screening data.
Related Articles Druggability indices for protein targets derived from NMR-based screening data.
J Med Chem. 2005 Apr 7;48(7):2518-25
Authors: Hajduk PJ, Huth JR, Fesik SW
An analysis of heteronuclear-NMR-based screening data is used to derive relationships between the ability of small molecules to bind to a protein and various parameters that describe the protein binding site. It is found that a simple model including terms for polar and apolar surface area,...
Protein-observed 19F-NMR for fragment screening, affinity quantification and druggability assessment - Nature.com
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