Small-molecule design for NMR fragment-based lead discovery

NMX是一家位于蒙特利尔和波士顿的翻译合同研究机构(CRO)。作为生物制药部门的一部分，NMX通过提供以客户为基础的服务和合作伙伴关系，为未来药物的热门和线索发现提供支持和加速小分子药物的发现。发现我们未来药物最有希望的策略之一是通过基于片段的先导发现(FBLD)，这是NMX开发的一项创新技术。FBLD涉及对小分子文库的筛选，以首先确定与疾病的基本目标蛋白的弱结合。然后通过药物化学设计努力，将这些粘合剂合成成更大、更有效的抑制剂/先导化合物。然而，在实现这一关键步骤方面存在重大瓶颈，这阻碍了许多制药科学家追求这一方法。这是因为实验技术在正确描述高浓度下的弱粘结剂方面是出了名的不可靠。NMX建议通过重新定义FBLD每一步的基本技术来解决这个问题。设计了文库，实施了新的核磁共振筛选策略，并开发了分析软件。这些努力将使药物化学家能够轻松地建立结构-活性关系(SAR)，这对于将粘合剂提供给药物先导是至关重要的。然而，为了优化这些努力产生的结果，核磁共振筛选策略的实施不能完全使用商业上可用的化合物。此外，进一步用于创新应用的生物活性分子的功能化(如蛋白水解靶向嵌合体，PROTAC)是复杂的，因为它不仅需要通过SAR修饰生物活性分子的经验，而且还需要仔细设计/合成具有适当化学功能的双功能连接物，以共价连接最有希望的HITS。因此，迫切需要实施创新的合成策略，以精制具有优异药物性质的修饰片段(HITS)，Castonguay博士将带来NMX团队目前无法提供的化学专业知识。

NMX is a translational contract research organization (CRO) located in Montreal and Boston. As part of the biopharmaceutical sector, NMX enables and accelerates small- molecule drug discovery by providing client-based services and partnerships for discovering hits and leads for future drugs. One of the most promising strategies for discovering our future medications is via fragment-based lead discovery (FBLD), an innovative technique exploited by NMX. FBLD involves the screening of libraries of small molecules to first identify weak binders to essential target proteins of diseases. These binders are then synthetically matured to larger, more potent inhibitors/leads via medicinal chemistry design efforts. However, there are major bottlenecks to achieving this critical step which have discouraged many pharmaceutical scientists from pursuing this approach. This is because experimental techniques are notoriously unreliable at properly characterizing weak binders at high concentrations. NMX proposes to tackle this issue by redefining the fundamental techniques at each step of FBLD. Libraries are designed, new NMR screening strategies are implemented and analysis software are developed. Together these efforts will enable medicinal chemists to easily establish structure-activity relationships (SAR), which is crucial for rendering binders to drug leads. However, in order to optimize results arising from these efforts, the implementation of NMR screening strategies cannot be achieved with the exclusive use of commercially available compounds. Moreover, the functionalization of bioactive molecules for further use in innovant applications (such as proteolysis targeting chimera, PROTAC) is complex, as it will not only require experience with the modification of bioactive molecules via SAR, but also with the careful design/synthesis of bifunctional linkers with the proper chemical functionalities to covalently link the most promising hits. Thus, there is a critical need to implement innovant synthetic strategies for the elaboration of modified fragments (hits) with superior drug-like properties, and Dr. Castonguay will bring an expertise in chemistry which is not currently available within the NMX team.