Applying phenotypic screens as a strategy to identify potential drug candidates continued to gain attention in recent years. The ultimate goal of this approach is to identify chemical matter correcting disease-relevant cellular phenotypes with the potential to be truly disease-modifying. Thus, industry has established innovative and novel disease-relevant screening paradigms along with target identification methods. The combined strategy of high-end phenotypic screens, enabled by high content screening technologies including cell painting approaches, followed up by medicinal chemistry optimisation based on poly-pharmacology models and relevant biological assays to the identification of molecular targets has posed a challenge for many years. Today a number of sophisticated technologies are available to support each of the individual steps of that process.
The presentation will discuss and differentiate these technologies for its drug discovery potential. Particular focus will be given to high content screening approaches and data analysis algorithms combined with quantitative mass spectrometry based chemical proteomics to identify the target(s) of small molecule hit compounds. The technologies use cellular background to reveal a compound's cellular binding partners including binding affinities thus allowing deciphering the network of intracellular targets and enabling lead optimization.