Abstract
In the past several years nuclear magnetic resonance (NMR) spectroscopy has emerged as a valuable tool in the drug discovery field. In such context, several NMR-based techniques have been developed aimed at the identification and subsequent optimization of novel binders for a given protein target. Among the different NMR approaches, those relying on the transferred Nuclear Overhauser Effect (tr-NOE) appear to be particularly useful as in some instances, in addition to binding, tr-NOE may provide also structural information on the binding mode of a ligand. In the current work we will reiterate the basic principles and applications that are related to measurements of tr-NOEs. The tr-NOE can be applied as a screening tool to recognize ligands for a given target protein in a mixture of compounds or to identify pair of molecules that bind to a protein simultaneously on adjacent sites (interligand NOEs). Moreover, in the case of peptide-ligands, tr- NOEs furnish intra-molecular distance constraints that can be used to determine their bioactive conformation. Starting from the conformation thus obtained, a pharmacophoric model can be derived and later used to search within a 3D database of small molecules to find new potentially active non-peptide compounds that fit the pharmacophore. We will report examples of each of the above mentioned strategies.
Keywords: NMR-based approaches, Saturation Transfer Difference (STD), Interligand NOEs, software DYANA, drug discovery
Current Drug Discovery Technologies
Title: The Nuclear Overhauser Effect in the Lead Identification Process Pharmacophore Models
Volume: 3 Issue: 2
Author(s): Marilisa Leone, Hudson H. Freeze, Chui Sien Chan and Maurizio Pellecchia
Affiliation:
Keywords: NMR-based approaches, Saturation Transfer Difference (STD), Interligand NOEs, software DYANA, drug discovery
Abstract: In the past several years nuclear magnetic resonance (NMR) spectroscopy has emerged as a valuable tool in the drug discovery field. In such context, several NMR-based techniques have been developed aimed at the identification and subsequent optimization of novel binders for a given protein target. Among the different NMR approaches, those relying on the transferred Nuclear Overhauser Effect (tr-NOE) appear to be particularly useful as in some instances, in addition to binding, tr-NOE may provide also structural information on the binding mode of a ligand. In the current work we will reiterate the basic principles and applications that are related to measurements of tr-NOEs. The tr-NOE can be applied as a screening tool to recognize ligands for a given target protein in a mixture of compounds or to identify pair of molecules that bind to a protein simultaneously on adjacent sites (interligand NOEs). Moreover, in the case of peptide-ligands, tr- NOEs furnish intra-molecular distance constraints that can be used to determine their bioactive conformation. Starting from the conformation thus obtained, a pharmacophoric model can be derived and later used to search within a 3D database of small molecules to find new potentially active non-peptide compounds that fit the pharmacophore. We will report examples of each of the above mentioned strategies.
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Cite this article as:
Leone Marilisa, Freeze H. Hudson, Sien Chan Chui and Pellecchia Maurizio, The Nuclear Overhauser Effect in the Lead Identification Process Pharmacophore Models, Current Drug Discovery Technologies 2006; 3 (2) . https://dx.doi.org/10.2174/157016306778108884
DOI https://dx.doi.org/10.2174/157016306778108884 |
Print ISSN 1570-1638 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6220 |
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