Development of biophysical assays for fragment-based lead discovery strategies

开发基于片段的先导化合物发现策略的生物物理测定

• 批准号: 521180-2017
• 负责人: Bourgault, Steve
• 金额: $ 1.82万
• 依托单位: Université du Québec à Montréal
• 依托单位国家: 加拿大
• 项目类别: Engage Grants Program
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=639703
• 关键词: Development; biophysical; assays; fragment; based

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.

NMX Research and Solutions（NMX）是加拿大的一家转化研究机构，为药物发现提供开发，包括先导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），它提供有关化合物溶液性质和与靶生物分子相互作用的原子级信息。在过去的几年里，NMX开发了一个独特的NMR策略工具箱，以确保提供高质量的命中和线索。这些基于核磁共振的药物发现配体筛选的综合策略现在需要得到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，以启动一项新的研究，以支持他们的创新NMR方法，用于定量测定小分子结合亲和力和结合动力学。在过去的几年里，昆士兰大学的Bourgault博士的分析生物化学实验室在生物分子相互作用的生物物理分析方面积累了专业知识，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的配体，同时开发SPR和ITC策略以及基于NMR的基于片段的先导发现策略-7.SPR和ITC是研究分子间相互作用和测定结合亲和力（Kd）的最新技术。然而，筛选低分子量化合物的结合，如使用基于基础设施的先导发现策略，是非常具有挑战性的，需要创新的技术和多轮优化。此外，许多药物靶标在溶液中自组装成寡聚体状态（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药理学方法所得结果联系起来的尝试都变得微不足道。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NMR的筛选平台，我们将获得这些生物物理技术之间独特和前所未有的直接相关性。