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Drug discovery

Sifting through chemical kaleidoscopes

Munich, 09/03/2012

LMU researchers have developed a new and highly efficient drug screening method. The technique can identify drug candidates in so-called dynamic compound libraries even when the target molecule itself is present only in extremely low concentrations.

Effective drugs act by binding tightly and specifically to particular biomolecular targets. That is why binding studies, which measure the affinities of potential drug candidates for a specific target molecule, are one of the mainstays of drug screening. Several different approaches can be used to determine binding affinities, and LMU pharmacist Professor Klaus Wanner previously developed MS binding assays, a strategy based on the use of mass spectroscopy, which avoids the need to label test substances with radioactive isotopes.

In its original form, the method had only been applied to one test compound at a time. Wanner and his team have now adapted the technique for use on whole sets of substances simultaneously. The strategy utilizes “dynamic combinatorial libraries” of test substances - collections of compounds formed by linking diverse molecular modules of two different types together by means of a single, reversible reaction. This allows the bipartite compounds to be readily broken up and the fragments rejoined in different combinations, generating a kaleidoscope of agents for screening.

Aiming at low concentrated targets
The normal way to screen such a library is to monitor how its composition is altered when the synthetic reaction is performed in the presence of the target. “This kind of analysis can be quite complicated, especially if the target can only be introduced in low concentrations, as is usually the case with membrane-bound targets,” says Wanner. To obtain reliable binding data, the LMU team applied reaction conditions which ensured that the libraries were “pseudostatic” and all test compounds were present in comparable amounts.

Wanner and his colleagues were able to detect binding reactions even when the target was present in very low concentrations. The new method therefore permits faster and more efficient identification of model structures for drug development. Furthermore, the technique can, in principle, be applied to any type of target. In the new study, the approach led to the identification of two new lead compounds for the development of pharmacologically useful drugs. (ChemMedChem, 3. September 2012) göd


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