An early step in drug discovery is to find a compound that binds to a drug target. So, seeking more “shots on goal,” pharmaceutical companies have been expanding their compound libraries, often to more than a million compounds. Laboratory screening of so many compounds against molecular targets demands miniaturization of compound samples to the smallest possible liquid volumes. Smaller samples facilitate industrial-scale screening because they can be dispensed onto the densely arrayed plates used in the screening process. Smaller samples also reduce the cost of acquiring compounds and eventually disposing of them. Whereas a decade ago GSK would use 50 microlitres of a compound for a single test of it against a target, the company today uses 5 microlitres (5 millionths of a litre), about the volume of ink needed for 100 signatures.
Now that volume stands to shrink even further, owing to still newer dispensing techniques. One of them is called acoustic droplet ejection. The short video here captures it: the compound sample as it lifts off from a source-well, buds into a droplet, and flies toward an inverted “target plate” directly above the source-well. (The plate is not in view in this video.) As of now, the volume of the droplet ejected for a single assay is 50 nanolitres, but the goal is to reduce it still further—to as little as 2.5 nanolitres (2.5 billionths of a litre). How little is that? Imagine the period at the end of this sentence in three dimensions, that is, volumetrically. It could easily hold several 2.5-nanolitre droplets. In addition to reducing volumes, the dispensing technique shown in the video guards against contamination and clogging of pipettes. For, of course, there are no pipettes. Instead, a transducer positioned below the source-well converts radiofrequency energy into an acoustic wave that launches each droplet. The droplet then adheres to the inverted plate by surface tension. Subsequent steps of the screening process add to the plate a buffer and then, finally, an assay incorporating the target, such as an enzyme or a cell-surface receptor.
If the compound sample binds to the target, that binding is a “hit”—an initial, encouraging sign in drug discovery. Nevertheless, even if the hit is the beginning of a medicine, some 10 to 20 years of further research and development will typically lie ahead.
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