Hit Discovery

The identification of "Hits" is the starting point for small molecule drug discovery.  A hit is usually defined as a molecule which binds to the target, which has been identified to be important in the disease of interest. Until recently, hits were identified by randomly screening millions of compounds against a target.  In practice, this has yielded fewer hits than expected so a new tailored approach has emerged. 

UCB has put in place a basket of technologies one or all of which may be applied depending on the target. 

A brief overview of UCB's Hit Identification capabilities

The starting point for hit discovery is the availability of a suitable compound collection. UCB's current compound library covers a broad spectrum of targets from enzymes and receptors to adhesion molecules and ion channels and it is continuously being enhanced and expanded.  This compound library can then be screened to provide hits.

Each research site has the infrastructure to quickly perform medium throughput screens (MTS, approximately 40,000 compounds) and UCB has a global HTS facility based in Braine, near Brussels (100,000 - 1,000,000 compounds).  

The Chemical Universe

Drug discovery is finding the right chemical for the right disease.  Since the number of possible compounds is almost unimaginable, no one chemist could ever make a fraction of this number.

UCB has identified core fragments of drugs, particularly the structures that are known to be safe and effective that can be synthesised in the laboratory.  By entering this information in a base it now becomes possible to consider all the possible drug molecules and evaluate them in the computer to assess their suitability as a hit (Virtual Screening Collection).  With each molecule having been assigned to a position in space, UCB chemists can now navigate the chemical universe and identify opportunities to change our molecules and therefore develop drugs of the future.

Virtual screening

UCB uses a parallel computing process to perform virtual screening. This allows us to select those molecules most likely to have the activities we desire. These compounds are selected from our compound collection synthesised or acquired by UCB and from a base we have created of all available commercial compounds.

Fragment screening

Screening of compound fragments (molecular weight <300Da) has rapidly gained acceptance in the industry as a means of generating chemical hits.  Fragment-based drug discovery is focused on binding efficiency rather than potency alone.  Larger drugs, often designed with a particular target in mind, are precluded from most binding sites because of their size and any interactions between the protein and target are likely to be limited. But fragments ("fragments of drugs") may have significantly greater affinity to the binding site, partly because of their small size, and can be used as the initial building blocks for a new drug.

The method of choice for fragment screening is NMR and this is performed using UCB's fragment library.  Combining this with structure-based drug design, for example, crystallography, results in a very powerful tool.

UCB makes use of a new way to screen using NMR in a collaboration using the technology developed by Zobio. This technique called target immobilised NMR Screening (TINS) uses a porous solid to immobilise the target protein along with a reference protein.  A mixture of compounds is injected and then split in two so it flows over both target and reference.  Those that bind specifically to the target can then be identified.  This is a simple, efficient and rapid process by NMR standards and requires relatively small amounts of the target protein.