The Nuclear Overhauser Effect in the lead identification process.
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.
Leone
Marilisa
M
Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Freeze
Hudson H
HH
Chan
Chui Sien
CS
Pellecchia
Maurizio
M
D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D011487:Protein Conformation; D013678:Technology, Pharmaceutical / Q000379:methods* / Q000639:trends
D010455:Peptides