Angewandte Chemie International Edition

Cover image for Vol. 54 Issue 37

Editor: Peter Gölitz, Deputy Editors: Neville Compton, Haymo Ross

Online ISSN: 1521-3773

Associated Title(s): Angewandte Chemie, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemistryOpen, ChemPlusChem, Zeitschrift für Chemie

For full article and contact information, see Angew. Chem. Int. Ed. 2002, 41 (18), 3420 - 3423; 3454 - 3457

No. 18/2002

A Probe for the Needle in a Haystack

Two new NMR screening methods to search
for pharmaceutical agents in substance libraries

The search for new pharmaceutical agents is similar to the proverbial search for a needle in a haystack. Today, rather than blindly poking around in the hay, the search for substances (ligands) that bind a specific protein associated with a disease, for example, is carried out very systematically. In order to test as many potential ligands as possible in the shortest possible time, large numbers of related compounds, so called substance libraries, are examined together and the "active" molecules (hits) fished out by some screening technique. The problem is to develop a rapid, sensitive and reliable screening method. Teams working with Wolfgang Jahnke at Novartis Pharma AG in Basel and Aloysius Siriwardena at the Complex Carbohydrate Research Center, University of Georgia (USA) have now developed two new, nuclear magnetic resonance (NMR) based screening variations.

Common to both methods is the same clever approach: both the target protein and a known, weakly binding ligand are added to the test substances in a given library. The known ligand acts as a sort of probe; if the library contains a substance that binds more strongly than the probe, the probe molecule will be forced out of its binding site, and will thus be free in the solution. This can be detected by means of changes in the NMR spectrum of the probe. It is even possible to quantify the strength of the binding between any hit and the protein by this method. If there are no suitable ligands in the library, the probe's spectrum remains unchanged.

The two methods, both described in Angewandte Chemie, differ in the spectral changes that are followed. The American researchers observe the increase in height of a specific peak in the NMR spectrum of their probe, which is dependent on the number of unbound probe molecules. The Swiss researchers found that under the conditions of their test system, it made the most sense to follow the decrease in the linewidths in the probe's spectrum, as the sharpness of the peaks increases as the proportion of free probes increases.

Aside from their remarkable speed, both probe-based NMR screening techniques have the advantage of offering substantially more accurate hit ratios than methods in which the NMR spectra of the test substances are used directly. The search for biologically active substances is a bottleneck in pharmaceutical research - these new techniques could remedy this.