Protein-protein interactions (PPIs) are at the center of almost every cellular process from cell proliferation to cell metabolism and even signal transduction pathways. Thus it is not surprising that PPIs are of pivotal importance in the development of most diseases. In particular, many intracellular PPIs are compelling targets for the development of cancer therapeutics and neurodegenerative diseases. PPIs are generally considered as challenging and most of them are thought to be undruggable targets. Recently there has been substantial progress and the first PPI inhibitors have reached clinical development. Although identifying effective inhibitors for PPIs still remains a challenge. Even if small molecules are available, which bind and inhibit PPIs. Most of them lack the potential to become drugs because of enormous difficulties to overcome major obstacles.
Some inhibitors have a potency only in the micromolar range and improvement of their affinity towards the target with medicinal chemistry was unsuccessful. Other inhibitors contain structural elements identified as pan assay interference compounds (PAINs), which have the potential to interfere with biological assays.
When screening for PPI modulators, binding of the small molecule does not automatically translate into a functional effect. Therefore, we use a combination of particular functional screens and binding assays.
We rationally select hot spots on the drug target to identify small molecules. Hot spots are specific residues or regions, which are mainly responsible for driving binding between proteins though providing disproportionately more binding energy than other areas of the protein.