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April 16, 2012
Phenotypic Screening's Comeback
Here's an excellent overview of phenotypic screening at SciBx. For those outside the field, phenotypic screening is the way things used to be all the time in the drug discovery business, decades ago: (1) give compounds to a living system, and watch what happens. (2) Wait until you find a compound that does what you want, and develop that one if you can.
That's as opposed to target-based drug discovery, which began taking over in the 1970s or so, and has grown ever since as molecular biology advanced. That's where you figure out enough about a biochemical pathway to know what enzyme/receptor/etc. you should try to inhibit, and you screen against that one alone to find your leads. That has worked out very well in some cases, but not as often as people would have imagined back at the beginning.
In fact, I (and a number of other people) have been wondering if the whole molecular-biology target-based approach has been something of a dead end. A recent analysis suggested that phenotypic screens have been substantially more productive in generating first-in-class drugs, and an overemphasis on individual targets has been been suggested as a reason for the lack of productivity in drug discovery.
As that new article makes clear, though, in most cases of modern phenotypic screening, people are going back from their hit compounds and finding out how they work, when possible. That's actually an excellent platform for discoveries in biology, too, as well as for finding medicinally active compounds. I'm glad to see cell- and tissue-based assays making a comeback, and I hope that they can bail us all out a bit.
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