Small-molecule design for NMR fragment-based lead discovery

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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.