Drug Discovery - Chemical Proteomics

Developing new drugs is a challenging project. The old-school way was defining a target protein, making the target protein, developing an assay and then looking for the inhibition of the activity by a small molecule. Medical chemistry synthesised many millions of drug-like molecules, very few make it to the clinics or into the pharmacies, most fail. Why do they fail, several reason.
The most negative reason are the side-effects, like toxicity. Side-effects can be explained by the unwanted interaction of the drug candidate with another protein in the complex cellular system. There are many examples, some side-effects became only visible after a longer time or did not affect the user directly, but the child of the pregnant woman.
Identifying potential off-targets, which are the cause of the side-effects, is essential and in early drug development phases can reduce costs and speed up the process.

Chemical Proteomics is one way to identify off-targets in an early phase. The essential question here is:

Which proteins in a cell, in an organism interact with my small molecule

Two approaches to identify these off-targets on a cellular, tissue or organ level have been developed.

The first one is based on affinity chromatography, the drug candidate is immobilised on a matrix and the proteins from the cell, tissue or organ lysate binding to it are identified by mass spectrometry in the described Proteomics way. This has been applied in many cases.
The major problem is the immobilisation of the small molecule, very often a linker has to be attached and even more difficult the linker has to be attached on several sites of the molecule. This requires medical chemistry as very often the molecule needs to be synthesised from scratch.
Several derivatives of this technique have been applied, for detailed questions, contact us.

The other technique does not require any chemical modifications of the drug candidate. It is based on the fact that proteins having bound a small molecule ligand gets stabilised, they denature at higher temperatures than the protein without bound ligand. Cells or cell lysates are incubated with the molecule, then proteins without bound ligand are precipitated with increasing temperatures and the proteins with bound ligand are staying in solution and get identified by mass spectrometry.

Bothe techniques can be applied in early drug development phases and give comprehensive information about targets and off-targets and explain toxicity in an early state.