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Concept
Phenotypic screening
Summary
Phenotypic screening is a type of screening used in biological research and drug discovery to identify substances such as small molecules, peptides, or RNAi that alter the phenotype of a cell or an organism in a desired manner. Phenotypic screening must be followed up with identification (sometimes referred to as target deconvolution) and validation, often through the use of chemoproteomics, to identify the mechanisms through which a phenotypic hit works.
Phenotypic screening historically has been the basis for the discovery of new drugs. Compounds are screened in cellular or animal disease models to identify compounds that cause a desirable change in phenotype. Only after the compounds have been discovered are efforts made to determine the biological targets of the compounds - a process known as target deconvolution. This overall strategy is referred to as "classical pharmacology", "forward pharmacology" or "phenotypic drug discovery" (PDD).
More recently it has become popular to develop a hypothesis that a certain biological target is disease modifying, and then screen for compounds that modulate the activity of this purified target. Afterwards, these compounds are tested in animals to see if they have the desired effect. This approach is known as "reverse pharmacology" or "target based drug discovery" (TDD). However recent statistical analysis reveals that a disproportionate number of first-in-class drugs with novel mechanisms of action come from phenotypic screening which has led to a resurgence of interest in this method.
The simplest phenotypic screens employ cell lines and monitor a single parameter such as cellular death or the production of a particular protein. High-content screening where changes in the expression of several proteins can be simultaneously monitored is also often used. High-content imaging of dye-labeled cellular components can also reveal effects of compounds on cell cultures in vitro, distinguishing the phenotypic effects of a broad variety of drugs.
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