Drug Discovery

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What is Drug Screening?

Screening in drug discovery refers to the selection of compounds with desired properties from a large number of compounds. There are various methods for screening, and it is important to select the most appropriate method according to the stage and purpose of drug discovery research.

When a disease-causing target (receptor, enzyme, ion channel, etc.) is known, screening is performed by analyzing interactions with that target. This is called target-based screening. On the other hand, phenotypic screening is used when the target is unknown. In addition, pharmaceutical companies may screen an enormous number of compounds, ranging from tens of thousands to millions. This method is called high-throughput screening (HTS) and is used as the primary screening process in drug discovery research.

Target-based Screening

Target-based screening involves identifying a target molecule that causes a disease, and conducting screening based on functional changes in the target molecule as an indicator. This method has become the mainstream approach in drug discovery research. For example, in an evaluation system using a target enzyme and its substrate, inhibitory effects on the enzyme can be measured by adding compounds and measuring the changes in the amount of substrate. Cells that express or have been manipulated to express the target molecule can also be used to measure specific changes caused by compounds.

Phenotypic Screening

While target-based screening is focused on specific targets, phenotypic screening is a method that screens for phenotypic changes in cells, organs, etc. as indicators without identifying target molecules. In phenotypic screening, cell models that recapitulate the characteristics of the disease are established, and then compounds are screened based on changes in indicators such as cell proliferation and cell death. In addition, recent advances in technologies to produce stem cells, such as ES cells and iPS cells, have made it possible to conduct screening in conditions that more closely reproduce human diseases. In phenotypic screening, the targets of the hit compounds are unknown, making it necessary to establish a method to identify the targets.

	Advantage	Disadvantage
Target-based Screening	High throughput Clear mechanism of action of hit compounds	Limited number of target molecules Unclear whether hit compounds alter disease phenotype
Phenotypic Screening	Compounds with novel mechanisms of action are obtained. Screening is possible even if the phenotypic mechanism is unknown.	Low throughput Evaluation is needed to identify the mechanisms of action of hit compounds.

High-throughput Screening (HTS)

Pharmaceutical companies have libraries of tens of thousands to millions of compounds, and HTS is a method for rapidly evaluating such huge numbers of compounds. In HTS, robots are used to automate the operations to allow large numbers of compounds to be evaluated.