Protein-protein interaction modulator drug discovery: past efforts and future opportunities using a rich source of low- and high-throughput screening assays.
BACKGROUND
Historically, small-molecule drug discovery projects have largely focused on the G-protein-coupled receptor, ion-channel and enzyme target classes. More recently, there have been successes demonstrating that protein-protein interactions (PPIs) can be targeted by small-molecules and that this strategy has the potential to provide appropriate specificity and selectivity. However, a disadvantage is that compounds that modulate PPIs are often associated with relatively weak affinities as the targeted interaction surfaces are often relatively large. Moreover, from a small-molecule screening perspective, a large proportion of the initial screening Hits are often false positives and these need to be identified and excluded in order to focus on genuine modulators of the PPI being investigated.


METHODS
The authors review previous efforts on PPI modulator drug discovery. Furthermore, they review assays that can be employed in small-molecule screening and/or Hit validation. The PPI assays are categorized as: i) low-throughput target-based biochemical assays, which are primarily employed for Hit validation at the post-screening stage; ii) high-throughput target-based biochemical assays that are suitable for screening campaigns; and iii) cell-based assays, which are suitable for high-throughput screening campaigns and/or Hit validation.


CONCLUSIONS
Modulating the interaction of PPIs offers the potential to develop novel drugs to treat a wide range of diseases. New assay technologies are continually being developed and it is anticipated that these will be able to be directly used for small-molecule screening campaigns in the future.
Fraunhofer Institute for Molecular Biology and Applied Ecology ScreeningPort (Fraunhofer-IME SP) , Schnackenburgallee 114, D-22525 Hamburg , Germany.
Sheraz
S
Gul
Kamyar
K
Hadian
D001681:Biological Assay; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D025941:Protein Interaction Mapping; D011506:Proteins / Q000378:metabolism
D011506:Proteins
assay formats; drug discovery; high-throughput screening; protein–protein interaction; small-molecule libraries