Drug Discovery Screening
Once a biochemical or cell-based assay has been developed successfully, the lead identification, or screening, process begins. Primary screens identify hits. Subsequently, confirmation screens and counter screens identify leads out of the pool of hits. This is commonly referred to as the "hit-to-lead" process. The success of drug discovery screening depends on the availability of compounds, as well as their quality and diversity. Efforts to synthesize, collect, and characterize compounds are an essential and costly part of drug discovery.
The goals of primary screens are to minimize the number of false positives and maximize the number of confirmed hits. Typically, primary screens are run in multiplets (i.e., two, three, or more) of single compound concentrations. Readouts are expressed as percent activity in comparison to positive and negative controls. Hits are retested independently of the first assay. If a compound exhibits the same activity within a statistically significant range, it is termed a confirmed hit. The next step is dose-response screening, typically referred to as a secondary screen.
In a secondary screen, a range of compound concentrations is tested in an assay to assess the concentration or dose dependence of the assay's readout. Typically, this dose-response is expressed as an IC50 in enzyme-, protein-, antibody-, or cell-based assays, or as an EC50 in in vivo experiments. The shape of a dose-response curve often provides information about the mechanism of action.
Confirmed hits are then profiled or run through a series of counterscreens. These assays usually include drug targets of the same protein or receptor family; for example, panels of GPCRs or kinases. These screens profile the action of a confirmed hit on a defined spectrum of biological target classes. Counterscreens can also be used to confirm mechanism of action.
Mechanism of Action
One of the goals throughout the discovery of novel drugs is to establish and confirm the mechanism of action. In an ideal scenario, the mechanism of action remains consistent from the level of molecular interaction of a drug molecule at the target site through the physiological response in a disease model.
Molecular Devices provides a range of bioanalytical systems to support primary and secondary screening, compound profiling, and mechanism of action studies.
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