An NMR strategy for fragment-based ligand screening utilizing a paramagnetic lanthanide probe.
J Biomol NMR. 2011 Sep 17;
Authors: Saio T, Ogura K, Shimizu K, Yokochi M, Burke TR, Inagaki F
Abstract
A nuclear magnetic resonance-based ligand screening strategy utilizing a paramagnetic lanthanide probe is presented. By fixing a paramagnetic lanthanide ion to a target protein, a pseudo-contact shift (PCS) and a paramagnetic relaxation enhancement (PRE) can be observed for both the target protein and its bound ligand. Based on PRE and PCS information, the bound ligand is then screened from the compound library and the structure of the ligand-protein complex is determined. PRE is an isotropic paramagnetic effect observed within 30*Å from the lanthanide ion, and is utilized for the ligand screening in the present study. PCS is an anisotropic paramagnetic effect providing long-range (~40*Å) distance and angular information on the observed nuclei relative to the paramagnetic lanthanide ion, and utilized for the structure determination of the ligand-protein complex. Since a two-point anchored lanthanide-binding peptide tag is utilized for fixing the lanthanide ion to the target protein, this screening method can be generally applied to non-metal-binding proteins. The usefulness of this strategy was demonstrated in the case of the growth factor receptor-bound protein 2 (Grb2) Src homology 2 (SH2) domain and its low- and high-affinity ligands.
PMID: 21927934 [PubMed - as supplied by publisher]
An NMR strategy for fragment-based ligand screening utilizing a paramagnetic lanthanide probe
An NMR strategy for fragment-based ligand screening utilizing a paramagnetic lanthanide probe
Abstract A nuclear magnetic resonance-based ligand screening strategy utilizing a paramagnetic lanthanide probe is presented. By fixing a paramagnetic lanthanide ion to a target protein, a pseudo-contact shift (PCS) and a paramagnetic relaxation enhancement (PRE) can be observed for both the target protein and its bound ligand. Based on PRE and PCS information, the bound ligand is then screened from the compound library and the structure of the ligandâ??protein complex is determined. PRE is an...
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09-20-2011 05:02 AM
An iminodiacetic acid based lanthanide binding tag for paramagnetic exchange NMR spectroscopy.
An iminodiacetic acid based lanthanide binding tag for paramagnetic exchange NMR spectroscopy.
An iminodiacetic acid based lanthanide binding tag for paramagnetic exchange NMR spectroscopy.
Angew Chem Int Ed Engl. 2011 May 2;50(19):4403-6
Authors: Swarbrick JD, Ung P, Chhabra S, Graham B
PMID: 21480444
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08-19-2011 02:56 PM
Cracking the molecular weight barrier: Fragment screening of an aminotransferase using an NMR-based functional assay.
Cracking the molecular weight barrier: Fragment screening of an aminotransferase using an NMR-based functional assay.
Cracking the molecular weight barrier: Fragment screening of an aminotransferase using an NMR-based functional assay.
Bioorg Med Chem Lett. 2011 Jul 21;
Authors: Mendoza R, Petros AM, Liu Y, Thimmapaya R, Surowy CS, Leise WF, Pereda-Lopez A, Panchal SC, Sun C
NMR-based screening of protein targets has become a well established part of the drug discovery process especially with respect to fragments. However, as target size increases...
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08-16-2011 01:19 PM
Rapid acquisition of (1) H and (19) F NMR experiments for direct and competition ligand-based screening.
Rapid acquisition of (1) H and (19) F NMR experiments for direct and competition ligand-based screening.
Rapid acquisition of (1) H and (19) F NMR experiments for direct and competition ligand-based screening.
Magn Reson Chem. 2011 Mar 9;
Authors: Dalvit C, Gossert AD, Coutant J, Piotto M
Direct and competition ligand-based NMR experiments are often used in the screening of chemical fragment libraries against a protein target due to the high relative sensitivity of NMR for protein-binding events. A plethora of NMR methods has been proposed...
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03-10-2011 03:51 PM
Target immobilization as a strategy for NMR-based fragment screening: comparison of TINS, STD, and SPR for fragment hit identification.
Target immobilization as a strategy for NMR-based fragment screening: comparison of TINS, STD, and SPR for fragment hit identification.
Target immobilization as a strategy for NMR-based fragment screening: comparison of TINS, STD, and SPR for fragment hit identification.
J Biomol Screen. 2010 Sep;15(8):978-89
Authors: Kobayashi M, Retra K, Figaroa F, Hollander JG, Ab E, Heetebrij RJ, Irth H, Siegal G
Fragment-based drug discovery (FBDD) has become a widely accepted tool that is complementary to high-throughput screening (HTS) in developing...
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01-13-2011 12:00 PM
Fragment-based discovery of novel thymidylate synthase leads by NMR screening and group epitope mapping.
Fragment-based discovery of novel thymidylate synthase leads by NMR screening and group epitope mapping.
Fragment-based discovery of novel thymidylate synthase leads by NMR screening and group epitope mapping.
Chem Biol Drug Des. 2010 Sep 1;76(3):218-33
Authors: Begley DW, Zheng S, Varani G
Solution-state nuclear magnetic resonance (NMR) is a versatile tool for the study of binding interactions between small molecules and macromolecular targets. We applied ligand-based NMR techniques to the study of human thymidylate synthase (hTS) using known...
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01-05-2011 09:51 PM
NMR Screening and Hit Validation in Fragment Based Drug Discovery.
NMR Screening and Hit Validation in Fragment Based Drug Discovery.
Related Articles NMR Screening and Hit Validation in Fragment Based Drug Discovery.
Curr Top Med Chem. 2010 Sep 2;
Authors: Campos-Olivas R
Over the past three decades nuclear magnetic resonance spectroscopy has been developed into a mature technique for the characterization of interactions of small molecule ligands with their corresponding protein and nucleic acid receptors. In fact, a significant number of industrial and academic laboratories employ NMR for screening small...
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09-03-2010 02:30 PM
[BMNRC community] NMR-based screening: a powerful tool in fragment-based drug discovery
NMR-based screening: a powerful tool in fragment-based drug discovery
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An NMR strategy for fragment-based ligand screening utilizing a paramagnetic lanthanide probe.
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