Drug Discovery Technique: High-Throughput Screening
See also: rational drug design, combinatorial chemistry

Lots of drugs today are discovered at random. That's right - by complete chance. Because it's cheaper and more effective than doing it rationally.

In the early ‘80s, companies were developing 3-D models of proteins attempting to design small compounds that would fit active sites on those proteins. By the late ‘80s, senior management teams saw that this approach wasn’t working well. It took 10-20 years to do and in the end, chemists weren’t successful. Then, one company came up with the idea that scientists weren’t smart enough to do rational drug design. So instead of trying to be clever, companies started to play a numbers game. They tried to create as many compounds as possible that looked like drugs and tested all of them against certain drug targets to see if any of them would inhibit the action of the target.

Today, this method is called high-throughput screening. The name itself is arbitrary – high-throughput is relative to what is considered a lot. Seven years ago, HTS was testing 50,000-60,000 compounds. Now, HTS tests 500,000 to 1,000,000 compounds in the same timeframe. The process is an evolutionary process – a population (300,000) of 300-700 dalton compounds is selected, then a selective pressure is applied in the form of a primary screen to select a smaller population (1,000) of compounds that affect the target.

This primary screen is followed by a series of 3-10 secondary screens that ask several questions. Is the compound what it seems to be? What is the toxicity of that compound? Is the compound’s effect nonspecific or is it selective to the protein of interest? What kinds of responses are elicited from different dosage levels? After all of these questions are answered, a hopeful 100-200 lead compounds will be left for chemists to perform lead optimization.

The chemists then figure out what fundamental structure is in common to all of the lead compounds. Combining techniques such as X-ray crystallography and 3D modeling with in-silico chemistry and other rational drug design techniques, chemists come up with structure activity relationships for the lead compounds and can adjust things like side groups to improve the potency and effectiveness of the leads. Those new and improved leads are then put through the entire process again in an iterative manner until the most promising leads are tested in animal models.

Gone are chemists with reactions in test tubes. Today, robots dispense chemicals into plates with 384 wells to run reactions. Advances in miniaturization have been critical to making hts a more efficient and viable technique. Since millions of reactions are run, each reaction must be run in miniature, at micro- or even nanoliter concentrations. That way, the total cost for chemicals for each reaction stays low, at under $.25 per reaction.

But once you start dealing liquids by the nanoliter, forces such as surface tension and static charges become so high that dispensing such small volumes of chemicals accurately becomes a problem. An entire field called microfluidics has sprung up to deal with moving nearly microscopic amounts of liquid.

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