Development of biophysical assays for fragment-based lead discovery strategies

NMX研究和解决方案（NMX）是一家加拿大的转化研究机构，提供药物发现的开发，包括先导药物的药物化学和命中的生物物理筛选。NMX的主要生物物理策略是核磁共振（NMR），它提供了化合物溶液性质和与目标生物分子相互作用的原子水平信息。在过去的几年中，NMX开发了一个独特的NMR策略工具箱，以确保交付高质量的命中和线索。这些基于senmr的药物发现配体筛选综合策略现在需要最先进的生物物理技术的支持。在这种情况下，NMX已经联系了Steve Bourgault博士，开始合作，以支持他们创新的NMR方法，用于定量测定小分子结合亲和力和结合动力学。Bourgault博士atUQÀM的分析生物化学实验室在过去几年中发展了生物分子相互作用的生物物理分析方面的专业知识，包括等温滴定量热法（ITC）和表面等离子体共振（SPR）。在这个项目中，我们将通过筛选小分子来鉴定半乳糖凝集素-7的配体，开发SPR和ITC策略与基于核磁共振的基于片段的先导物发现策略并行。SPR和ITC是研究分子相互作用和测量结合亲和力（Kd）的最新技术。然而，筛选低分子量化合物的结合，如使用基于片段的先导物发现策略，是非常具有挑战性的，需要创新的技术和多轮优化。此外，许多药物靶点自组装成低聚物状态（二聚体，四聚体），如半乳糖凝集素-7。这使得任何试图将不同生物物理方法得到的结果联系起来的尝试都显得微不足道。利用我们在分子相互作用表征方面的专业知识，我们将支持nmx开发其独特的基于核磁共振的筛选平台，我们将在这些生物物理技术之间获得独特且前所未有的直接关联。

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.