Fragment Based Drug Design: Approach and Description

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Recent years have seen a tremendous increase in the technologies available for the discovery of new drugs. Functional genomics research has led to the identification of an unprecedented number of potential therapeutic protein targets; combinatorial chemistry has expanded the size of compound collections; and high-throughput screening (HTS) has enabled the screening of million-compound libraries.

Fragment-based drug design is a new approach that has been successfully applied to challenging targets, such as protein-protein interactions. While 3-D protein structures have been used in drug discovery for many years now, fragment-based drug design uses x-ray crystallography or other physical techniques to screen fragment libraries for specific binding to a target protein. Knowledge of exactly how the fragments bind to the protein target allows the hits to be optimized by growing the fragments or by combining and linking different fragments.

Fragment-based drug design has a number of attractive features compared to high-throughput screening. The approach allows for the screening of substantially fewer compounds, usually several hundred to a thousand. It detects fragments that bind specifically but with low affinity (~100 µM to 10 mM). Low-affinity binders are generally difficult to detect by most other methods.

Obtaining structural information on the fragment complexed to the protein target is a key factor and also a major limitation. Therefore, computational methods are needed to mine efficiently all the available 3D structures of ligands complexed to proteins, both treated as a whole and as smaller fragment to increase the likelihood of fragment hopping from one target to another.

Within the space of only a few years, fragment-based drug design (FBDD) has emerged as an efficient and productive route for de novo drug discovery. Using tailored sets of chemical fragments FBDD is delivering high-quality drug leads against a multiplicity of new therapeutic targets in the pharmaceutical sector.

FBDD also offers the prospect of rapid hypothesis testing and validation of recently discovered molecular targets for use in drug discovery, of particular relevance for start-up biotechnology companies eager to add a new dimension to their discovery offerings.

In FBDD, researchers start with a library of a few thousand low-molecular-weight compounds, typically 100-300 Daltons each. They screen this small library against the target of interest to identify any fragments that bind, however weakly. Then they use structural information from X-ray crystallographic or NMR analyses to suggest ways of chemically improving these early-stage leads. After a few iterations of modifying the leads, boosting their affinity to the target and adding other drug-like properties, they hope to have found at least one compound that is worth taking forward.

Until now, many medicinal chemists didn't believe this would work. But in the last two years it has been demonstrated that you can go from a hit fragment with millimolar affinity to a compound with nanomolar affinity. Moreover, according to some researchers, this optimization can be done much more quickly and efficiently on fragments than on higher-molecular-weight candidates.

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Most research is being focused on one key problem: how to improve the potency of a hit fragment as quickly as possible. That requires knowing just how the fragment binds to its pocket in the target -- in particular, its orientation.

FBDD has developed over the last decade to take its place in the standard armoury of the pharmaceutical industry. It has yielded numerous, well-documented successes, and has proven to be the tool of choice for targets where much structural information is forthcoming, and which possess a well-defined, reasonably small binding site. Developments in high-sensitivity screening should now pave the way for the technique to be applied to a much wider range of targets than was previously possible. Careful design and selection of fragment collections should increase the overall efficiency of the process, as will the close coupling of SBDD techniques to direct the selection of fragments to screen, and subsequent fragment conglomerates to be created.

Fragment-based drug design is becoming an effective technology that is complementary to the existing approaches to drug design. It is clear that this technique will be used extensively in the future as more groups adopt the technology.

References:

http://www.iotapharma.com/literature

http://www.pharmadd.com/archives/May_16_2006/DM%20%20Fragment%20Bases%20Drug%20Design%20Delivers.asp

http://www.genengnews.com/articles/chitem.aspx?aid=1661&chid=1

http://www.solve.csiro.au/0807/article6.htm