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video 6 of 9 in drug discovery 101 playlist

learning objectives
describe the process of screening a library
summarize qualities of a screening assay
list types of compound libraries

Perhaps the most common starting point for a drug discovery program is the screening of a library of compounds with an assay. A compound library is exactly what it sounds like. It is not a library of books or Pokémon cards. It is a library or collection of molecules. These are molecules that can be individually sampled and tested using an assay. We’ll discuss libraries more on the next slide. In addition to the library, you do need an assay. Because compound libraries can be quite large, often over 100,000 compounds, the assay must be quick to perform and robust with few false positives or false negatives. Assays that fit these criteria can often be automated with robotic equipment to further facilitate the screening process. Note that each library compound is normally tested once at just a single concentration for the preliminary screen. Compounds that show a threshold level of activity in the assay are called “actives”. Let’s now focus on the compound libraries.

Libraries come in all different forms. The traditional compound library is used mostly by large drug companies. The company may have millions of compounds in its main library. The library is a historical record of compounds that the company has prepared and studied in the past. Because the full compound library is so vast and many of the compounds are very similar, large drug companies often have a smaller “screening collection”. The screening collection contains only representative compounds from similar structures in order to reduce the cost of screening. Sometimes scientists will select a “focused library” by only screening compounds with specific properties or structural features believed to be important for the target or discovery program.
“Fragment libraries” have become popular in the past 20 years or so. Fragments are smaller compounds with a molecular weight of 350 g/mol or lower instead of closer to 500 g/mol for traditional library compounds. Fragment libraries may require different assay technology but can provide advantages, including the fact that fragment libraries tend to be smaller with just a few thousand compounds instead of hundreds of thousands or more. A smaller library makes screening more accessible to smaller companies and even universities.

The final library type we’ll cover is the DNA-encoded library, called a DEL. DELs are a quite new library format. Each library member consists of both a segment of duplex DNA and the structure that binds the target. The DNA component is used to identify the target-binding structure. DELs can be immense libraries with over a billion members. The technology around preparing and testing individual compounds in DELs is still in its early stages, but DELs appear to be a promising tool for searching for compounds with favorable preliminary activity on an intended target.