The method of choice in drug-discovery in the past two decades has been target-based screening. Now, phenotypic screening is beginning to emerge as a preferable method.
Phenotypic screening involves the screening of a set of candidate molecules being tested based on its ability to exert effects. For example, testing a molecule in cells, isolated from tissues or organs, or animals, to test if molecule exerts side-effects. Historically, phenotypic screening held positive attributes in the identification of the first-in-class drugs, while target-based screening has yielded more best-in-class drugs which was due to the lack of bias when discovering a drug’s mechanism of action. But, phenotypic assays are more of an advantage with respect to the identification of cell active compounds, says Professor Elizabeth Sharlow from the University of Virginia School of Medicine, Virginia, USA.
“Phenotypic assays are challenging because of the need for, often, complicated downstream target deconvolution methodologies,” explains Professor Elizabeth Sharlow from the University of Virginia School of Medicine, “And they are also, in some instances, more time consuming to implement which in the long term may impact throughput. All of this needs to be factored into the overall screening paradigm and cost of the screening strategy.”
The genomic revolution in the last few decades has caused pharmaceutical companies and universities to adopt the ‘target-first’ approach. In other words, their method of reference in the drug discovery process was where a molecule known to be crucial in a disease process is used for screening vast compound libraries in the search for a ‘match’ a.k.a the candidate drug. One advantage to this method, is that many millions of drug-like molecules can be screened, knowing that if you get a match, you already have a potential drug. “Target-based assays, in general, are less time consuming to implement but sometimes are challenged by standard readouts such as enzymatic activity,” says out Professor Sharlow, “Then there’s more sophisticated target-based assays such as those based on protein-protein interactions, which, while more physiologically interesting, are much more complicated to implement.”
Overall, both screening strategies are important and necessary for chemical probe and the drug development process. However, there is still a slight rise in phenotypic screening. “Doing drug discovery screens within the cellular context already answers a few of the questions that bedevil the drug discovery process later on, such as ‘how do I make this more soluble?’, or ‘how do I get this into cells?’” explains Dr Mike Howell, Head of Screening at the Francis Crick Institute.
“If you’re a medicinal chemist, you’re probably correctly of the opinion that you can use your magic to make things that are not very soluble or are not very good at getting into cells, better at getting into cells. But there’s a feeling that if you start off with a good cell-based assay then you’ve leapt some of those hurdles inherently by design.”
