Oral 23rd International Society of Magnetic Resonance Conference 2023

19F NMR approaches to accelerate fragment-based drug design (#150)

Indu R Chandrashekaran 1 2 , Tsz Pun 1 2 , Evgenia Konstantinidou 1 2 , Kieren McDowell 2 , Imesha Hettige 1 2 , Luke A Adams 1 2 3 , Naureen Akhtar 2 , Menachem Gunzburg 2 3 , Bradley C Doak 2 3 , Martin J Scanlon 1 2 3
  1. ARC Centre for Fragment-Based Design, Monash Univeristy, Parkville, VIC, Australia
  2. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, Australia
  3. Monash Fragment Platform, Monash Univeristy, Parkville, VIC, Australia

Fragment-based drug design (FBDD) is a well-established approach to generate high quality starting points for drug discovery1. FBDD approach allows efficient exploration of chemical space thus increases the chances of identifying novel hits. Success of FBDD hinges on sensitive biophysical methods that can reliably detect and validate weak binding of fragments to the target of interest. NMR spectroscopy has been proven to be an invaluable biophysical tool in FBDD due to its detection capabilities and versatility2. NMR spectroscopy is a robust method that can identify, quantify and provide structural information on protein-small molecule interactions. In our group, we are exploring novel FBDD strategies to target a wide range of therapeutic targets. Our FBDD workflow utilises a variety of NMR methods including ligand-detected and protein-detected experiments employing both 1H and 19F detection. This is exemplified by FBDD on a soluble carrier protein, where fragments identified from a ligand-detected NMR screen has been successfully progressed to high affinity lead-like compounds. We highlight the impact of 19F NMR workflows on expediting fragment hit-to-lead development process and demonstrate that 19F NMR displacement assay is a robust method for quantifying binding affinities and determining selectivity.

 

 

  1. Erlanson, D. A.; Fesik, S. W.; Hubbard, R. E.; Jahnke, W.; Jhoti, H. Twenty years on: the impact of fragments on drug discovery. Nat Rev Drug Discov 2016, 15, 605-619.
  2. Harner, M. J.; Frank, A. O.; Fesik, S. W. Fragment-based drug discovery using NMR spectroscopy. J Biomol NMR 2013, 56, 65-75.