Development of biophysical assays for fragment-based lead discovery strategies

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NMX Research and Solutions (NMX) is a Canadian translational research organization that providesdevelopment for drug discovery, including medicinal chemistry for leads and biophysical screening for hits.The main biophysical strategies of NMX is nuclear magnetic resonance (NMR), which provides atomic-levelinformation about compound solution properties and interactions with target biomolecules. Over the last years,NMX has developed a unique toolbox of NMR strategies to ensure delivery of quality hits and leads. TheseNMR-based integrated strategies for ligand screening for drug discovery now need to be supported withstate-of-the-art biophysical techniques. In this context, NMX has contacted Dr. Steve Bourgault to initiate acollaboration in order to support their innovative NMR methods for quantitative determination of smallmolecule binding affinity and binding kinetics. The analytical biochemistry laboratory of Dr. Bourgault atUQÀM has developed over the last years an expertise in the biophysical analysis of biomolecular interactions,including isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR).In this project, we will develop SPR and ITC strategies in parallel with NMR-based fragment-based leaddiscovery strategies through the screening of small molecules to identify ligands of galectin-7.SPR and ITC are state-of-the-art techniques for studying molecular interactions and for measuring bindingaffinity (Kd). However, the screening of the binding of low-molecular weight compounds, as used infragment-based lead discovery strategies, is very challenging and requires innovative techniques and manyrounds of optimisation. Moreover, many drug targets self-assemble into oligomeric states (dimer, tetramer) insolution, as for galectin-7. This makes any attempts to correlate the results obtained from different biophysicalmethods all but trivial. Using our expertise in the characterization of molecular interactions, we will supportNMX in the development of their unique NMR-based screening platform and we will gain a unique andunprecedented direct correlation between these biophysical techniques.