Fragment Based Drug Discovery


Drug discovery using libraries of small molecule fragments with molecular weights of typically ≤300 Da offer an innovative approach to hit identification for a range of biological targets.

 

Sygnature Discovery offers FBDD as a cost effective alternative to other methods of hit identification.

 

Fragment-based drug discovery (FBDD) utilises a range of biophysical techniques, such as surface plasmon resonance (SPR), differential scanning fluorimetry (DSF) (also termed fluorescent thermal shift assay; FTSA), X-Ray crystallography and nuclear magnetic resonance (NMR), to screen fragment libraries for specific binding to a biological target.

The low complexity of these fragments increases the chance of complementarity to any protein surface; so it may only be necessary to screen several hundred molecular fragments, rather than the hundreds of thousands of compounds often tested during high-throughput screening (HTS) to obtain hits. This fragment-based hit-finding screen is often followed with X-ray crystallography to provide detailed knowledge of exactly how and where the fragments bind to a specific biological target. This structural information then facilitates the optimisation of these low affinity hits – either by careful growing off the fragments, or by combining different fragments together into one molecule.

The small size of the fragments makes subsequent expansion of the hits in an atom efficient manner, through the addition of well-matched functionality, more feasible. This contrasts with the slower, iterative cycles of piece-by-piece optimisation of a more complex, larger molecular weight hits (commonly identified by HTS). At Sygnature, this fragment hit optimisation process is particularly effective as our fragment library is proprietary and the novel fragments are well-designed for subsequent medicinal chemistry-driven expansion.


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