Fragment-Based Drug Design (FBDD)
Finding novel compounds as starting points for optimisation is the first major challenge in drug discovery research. Fragment-based methods have emerged in the past 20 years as an effective way to sample chemical diversity with a limited number of low molecular weight compounds. This information can be used to inform the design of new compounds with increased affinity, specificity and novelty, especially if the ternary complex structures of the fragments binding to the protein can be solved. In FBDD about 1000-1500 low molecular weight fragments are typically screened using structural biology and biophysical techniques. State-of-the-art 400 MHz and 600 MHz NMR with cryo-cooling is used in conjunction with SPR (Biacore 4000, 8k, T200) as our primary fragment screening technologies. Ideally, the experimental binding mode will be established by X-ray crystallography; however, in its absence NMR and docking techniques can be used to produce an initial binding mode. Using our profound expertise in structure-based design and medicinal and computational chemistry, fragments are grown to form new interactions, as shown schematically below. Although fragment hits have low potency due to their small size, they form high-quality interactions and can readily be optimised into potent lead molecules and ultimately clinical candidates.