Oral 23rd International Society of Magnetic Resonance Conference 2023

Targeting RNA using fragment-based drug discovery by NMR and SPR (#39)

Brooke Kwai 1 2 , Indu Chandrashekaran 1 2 , Biswaranjan Mohanty 2 3 , Menachem Gunzburg 2 4 , Bradley Doak 2 4 , Ashish Sethi 5 , Sean Harrison 6 , Pedro Serrano 6 , Shubhadra Pillay 7 , Elisa Barlie 7 , Martin Scanlon 1 2 4
  1. ARC Centre for Fragment-Based Design, Monash University, Melbourne, Victoria, Australia
  2. Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VICTORIA, Australia
  3. Sydney Analytical Core Research Facility, The University of Sydney, Sydney, NSW, Australia
  4. Monash Fragment Platform, Monash University, Melbourne, Victoria, Australia
  5. Australian Synchrotron, Australian Nuclear Science and Technology Organisation, Melbourne, Victoria, Australia
  6. Drug Discovery Sciences, Takeda Pharmaceuticals International Company, Massachusetts, Boston, USA
  7. Takeda California, Inc., California, San Diego, USA

Non-coding RNAs account for up to 80 % of the human genome.1 It has become increasingly clear that non-coding RNAs play a diverse and critical role in many important cellular functions.2 Although modulation of non-coding RNAs using small molecules has been demonstrated to be a promising therapeutic strategy, the structure-interaction relationships of RNA targeting small molecules remain largely unexplored.3 We hereby present a fragment-based drug discovery approach where NMR identified hits were validated and ranked by SPR, and binding poses were modelled using NOESY data in combination with molecular docking to evaluate and elaborate fragment hits against a theophylline aptamer model system. The methods used in this study have the potential to be applied to a variety of novel RNA targets.

  1. 1. Djebali S, Davis CA, Merkel A, et al. Landscape of transcription in human cells. Nature. 2012;489(7414):101-108. doi:10.1038/nature11233
  2. 2. Rizvi NF, Smith GF. RNA as a small molecule druggable target. Bioorg Med Chem Lett. 2017;27(23):5083-5088. doi:10.1016/j.bmcl.2017.10.052
  3. 3. Childs-Disney JL, Yang X, Gibaut QMR, Tong Y, Batey RT, Disney MD. Targeting RNA structures with small molecules. Nat Rev Drug Discov. 2022;21(10):736-762. doi:10.1038/s41573-022-00521-4