Related ArticlesLeveraging structural approaches: applications of NMR-based screening and X-ray crystallography for inhibitor design.
J Synchrotron Radiat. 2004 Jan 1;11(Pt 1):97-100
Authors: Moore J, Abdul-Manan N, Fejzo J, Jacobs M, Lepre C, Peng J, Xie X
In the last several years, NMR strategies in drug discovery have evolved from a primarily structural focus to a set of technologies that are non-structural in nature but that have a much greater impact on the identification and optimization of real drug leads. NMR-based screening methods, such as the SHAPES strategy, help rapidly identify good starting points for drug design in a relatively high throughput implementation. The SHAPES method uses simple NMR techniques to detect binding of a limited, but diverse library of low molecular weight, soluble compounds to a potential drug target. SHAPES library compounds are derived largely from molecular frameworks most commonly found in known therapeutic agents. The NMR experiments used in these protocols are based on the well-known NMR techniques, and may be applied to targets with no limitation on molecular weight and no requirement for isotope labeling. Following screening, SHAPES hits may be used to guide virtual screening, synthesis of combinatorial libraries, and bias the first compounds that undergo high throughput screening. Integration of the SHAPES strategy with iterative X-ray crystallographic structure determination can be very useful in deriving an initial structural pharmacophore model and achieving significant in vitro potency in a short time frame. Here, examples are provided of how the combination of NMR SHAPES screening, virtual screening, molecular modeling and X-ray crystallography has led to novel drug scaffolds in several drug discovery programs: JNK3 MAP kinase and the fatty acid binding protein, aP2.
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
[NMR paper] Sensitivity improvement in 19F NMR-based screening experiments: theoretical considerations and experimental applications.
Sensitivity improvement in 19F NMR-based screening experiments: theoretical considerations and experimental applications.
Related Articles Sensitivity improvement in 19F NMR-based screening experiments: theoretical considerations and experimental applications.
J Am Chem Soc. 2005 Sep 28;127(38):13380-5
Authors: Dalvit C, Mongelli N, Papeo G, Giordano P, Veronesi M, Moskau D, Kümmerle R
NMR-based binding and functional screening performed with FAXS (fluorine chemical shift anisotropy and exchange for screening) and 3-FABS (three fluorine atoms...
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12-01-2010 06:56 PM
[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,...
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11-25-2010 08:21 PM
[NMR paper] NMR-based screening methods for lead discovery.
NMR-based screening methods for lead discovery.
Related Articles NMR-based screening methods for lead discovery.
EXS. 2003;(93):183-202
Authors: Vogtherr M, Fiebig K
Diversity and robustness of NMR based screening methods make these techniques highly attractive as tools for drug discovery. Although not all screening techniques discussed here may be applicable to any given target, there is however a good chance that at least one of the described methods will prove productive in finding several medium affinity ligands. A comparison of each of...
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11-24-2010 09:01 PM
[NMR paper] Privileged molecules for protein binding identified from NMR-based screening.
Privileged molecules for protein binding identified from NMR-based screening.
Related Articles Privileged molecules for protein binding identified from NMR-based screening.
J Med Chem. 2000 Sep 7;43(18):3443-7
Authors: Hajduk PJ, Bures M, Praestgaard J, Fesik SW
A statistical analysis of NMR-derived binding data on 11 protein targets was performed to identify molecular motifs that are preferred for protein binding. The analysis indicates that compounds which contain a biphenyl substructure preferentially bind to a wide range of proteins and...
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11-19-2010 08:29 PM
An introduction to NMR-based approaches for measuring protein dynamics.
An introduction to NMR-based approaches for measuring protein dynamics.
An introduction to NMR-based approaches for measuring protein dynamics.
Biochim Biophys Acta. 2010 Nov 5;
Authors: Kleckner IR, Foster MP
Proteins are inherently flexible at ambient temperature. At equilibrium, they are characterized by a set of conformations that undergo continuous exchange within a hierarchy of spatial and temporal scales ranging from nanometers to micrometers and femtoseconds to hours. Dynamic properties of proteins are essential for describing the...
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11-10-2010 02:29 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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Leveraging structural approaches: applications of NMR-based screening and X-ray cryst
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