Drug discovery using libraries of molecular fragments of typically <=300 molecular weight (MW) offers an innovative approach to hit identification for a range of biological targets and is an alternative to other methods of hit identification.
For a number of years, 3D structures of biological targets, e.g. derived from X-ray crystallography, have been successfully applied during drug discovery. Fragment-based drug discovery utilises a range of biophysical techniques such as surface plasmon resonance (SPR), differential scanning fluorimetry (DSF) or nuclear magnetic resonance (NMR), to screen fragment-based libraries for specific binding to a biological target. This is often followed with X-ray crystallography to provide detailed knowledge of exactly how and where the fragments bind to a specific target. This facilitates the optimisation of these hits – either by elaborating the fragments, or by combining different fragments together into one molecule.
Fragment-based drug discovery offers an attractive alternative to HTS, in that it may only be necessary to screen several hundred molecular fragments, rather than the many thousands of compounds often tested during HTS. In addition, the small size of the fragments make subsequent chemical optimisation relatively straightforward because it is easier to expand small molecules in an atom efficient manner through the addition of well-matched functionality, rather than optimising and reducing the size of larger MW compounds. This approach is particularly effective if the fragments screened are novel and well-designed. Fragment-based technology is largely complementary to other ‘traditional’ drug discovery approaches, and is increasingly being used as more and more R&D groups adopt this methodology.