A fragmented approach to drug discovery

Wilkinson-White L1, Headey S2, Scanlon M2, Szyszka T3, Wai D3, Kwan A3 and Mackay J3

  1. Drug Discovery, Sydney Analytical Core Facility, University of Sydney.
  2. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University.
  3. School of Life and Environmental Sciences, University of Sydney.

In fragment based drug discovery (FBDD), a protein for which an inhibitor is sought is screened against a library of low molecular weight compounds known as fragments. The best fragment hits are then subsequently elaborated into higher affinity, larger ligands. Since the number of theoretical compounds increases exponentially with molecular weight, the screening of these smaller fragments allows for a much greater exploration of chemical space – meaning that fewer compounds need to be tested in order to identify initial hits. The Sydney FBDD platform is part of the Sydney Analytical Core Facility at the University of Sydney, and works in close collaboration with the Monash Fragment Platform (MFP) founded by A/Prof Martin Scanlon and colleagues at Monash Institute of Pharmaceutical Sciences (MIPS). We currently have several on-going projects targeting interactions for mammalian, bacterial and fungal proteins. One such project involves the ET domain of Bromodomain 3 (Brd3-ET). Brd3-ET plays a role in interacting with chromatin remodeling complexes, and the disruption of this interaction could lead to the development of novel cancer therapeutics. We have screened a fragment library curated by the MFP against Brd3-ET using an NMR Saturation-Transfer-Difference (STD) approach. Validation of hits has then been carried out using a combination of Triple-Ligand-Detect NMR, HSQC and Surface Plasmon Resonance. We have designed and tested analogues for our best validated hits, and are now in the process of combining structural information and medicinal chemistry to undertake further fragment elaboration, with the aim of developing therapeutics with high affinity and specificity.