Small-molecule design for NMR fragment-based lead discovery

NMX是一家位于蒙特利尔和波士顿的转译合同研究组织（CRO）。作为生物制药行业的一部分，NMX通过提供基于客户的服务和合作伙伴关系来发现未来药物的成功和线索，从而实现和加速小分子药物的发现。发现我们未来药物的最有希望的策略之一是通过基于片段的先导物发现（FBLD），这是NMX利用的一种创新技术。FBLD包括筛选小分子文库，首先确定疾病基本靶蛋白的弱结合物。然后通过药物化学设计的努力，将这些粘合剂合成成熟为更大、更有效的抑制剂/先导物。然而，实现这一关键步骤的主要瓶颈阻碍了许多制药科学家追求这种方法。这是因为实验技术在正确表征高浓度弱结合剂方面是出了名的不可靠。NMX建议通过重新定义FBLD每个步骤的基本技术来解决这个问题。设计了库，实现了新的核磁共振筛选策略，开发了分析软件。总之，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），这对于将结合剂转化为药物先导物至关重要。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仅使用市售化合物来实现。此外，生物活性分子的功能化以进一步用于创新应用（如靶向嵌合体的蛋白水解，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，还需要精心设计/合成具有适当化学功能的双功能连接体，以共价连接最有希望的命中。因此，迫切需要实施创新的合成策略，以细化具有优异药物样特性的修饰片段（击中），Castonguay博士将带来NMX团队目前无法获得的化学专业知识。

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.