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Current Drug Discovery Technologies

Editor-in-Chief

ISSN (Print): 1570-1638
ISSN (Online): 1875-6220

The Nuclear Overhauser Effect in the Lead Identification Process Pharmacophore Models

Author(s): Marilisa Leone, Hudson H. Freeze, Chui Sien Chan and Maurizio Pellecchia

Volume 3, Issue 2, 2006

Page: [91 - 100] Pages: 10

DOI: 10.2174/157016306778108884

Price: $65

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


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