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Drug discovery

Registering chemical pairings

Munich, 10/17/2012

In chemistry, as in life, not every encounter leads to stable bonding. But stable binding to a target is essential for drug action. An LMU team has now come up with an elegant way of measuring the affinities of ligands for their target proteins.

The average cell contains about 10,000 different kinds of proteins in a minute volume. And yet interactions with other proteins, small molecules and ions occur in ordered patterns.  This is possible because each protein species binds productively to only a relatively small number of partners. Effective drugs work on the same principle. A large part of drug development therefore involves determining how tightly and specifically candidate compounds bind to a given target. Ideally, a drug should bind to only one molecular target, as this minimizes side-effects.

A research team led by physicist Professor Dieter Braun and chemist Professor Dirk Trauner at LMU has developed a method that allows one to measure the binding of small ligands to proteins in their native state in solution. The technique does not require immobilization of the target, a step that may alter binding behavior. And, unlike conventional binding assays, in which a fluorescent label must be attached to the target, the method takes advantage of the UV fluorescence intrinsic to most proteins to track target molecules in the assay.

Putting the brakes on

A solution of the target protein is introduced into a glass capillary, and a known amount of the test substance is added. One end of the tube is irradiated with a laser, setting up a microscopic temperature gradient. The unbound protein diffuses down the gradient at a specific rate, which is altered by the binding of a ligand. Interestingly, ligands that bind to different sites on the same protein affect its diffusion rate in different ways. This enables one to distinguish the binding of different classes of drugs on the basis of the fluorescence signal.

The new thermophoresis-based method thus allows one to carry out measurements that were hitherto almost impossible. The assay is also easy to perform, and provides a tool that promises to improve our understanding of protein-ligand interactions. The label-free technique, called “microscale thermophoresis”, is particularly suitable for use in screening programs that involve large numbers of tests because each measurement requires only very small amounts of the target molecule.

The study was carried out by research groups led by Professor Dieter Braun, who is also affiliated with the Excellence Cluster “Nanosystems Initiative Munich (NIM)”, and Professor Dirk Trauner, also a member of the Excellence Cluster “Center for Integrated Protein Science Munich (CiPSM)”, in close cooperation with NanoTemper, an LMU spin-off.

(Angew. Chem. Int. Ed. 2012, 51)    NIM/suwe/PH


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