Fragment-Based Lead Discovery: Bridging the Gap Between Screening and Hit-to-Lead Medchem using NMR Affinity Ranking

Challenge: One of the most promising strategies for discovering our future medications is via fragment-based lead discovery (FBLD). FBLD involves the screening of libraries of small molecules to first identify weak binders, essential to activate or inhibit a target protein involved in a particular disease. These binders are then synthetically matured to larger, more potent inhibitors/leads via medicinal chemistry design efforts. However, major bottlenecks have discouraged industry from pursuing this approach, mainly because experimental techniques are notoriously unreliable at properly characterizing weak binders at the required high concentrations.

Solution: This project is tackling the issue by redefining the fundamental strategies at each step of FBLD. Fragment libraries are being appropriately designed and curated, new NMR screening techniques are being implemented, and analysis software are being developed. Together they are serving to offer a proper guidance in medicinal chemistry to screen and identify via innovative NMR Kd–SAR (structure-activity relationship) cycles, which are central to overcoming the hurdles of rendering binders to inhibitors. Thus, this project is implementing a holistic approach to characterize weak binders at high concentrations and thus enabling medicinal chemists to bridge historic gaps and identify leads.

Achievements/Impact: The team introduced new and improved approaches for FBLD. These will have a significant impact on FBLD, hit-validation, and more broadly on early-stage drug discovery strategies employed in industry and academia. The methods established in this project were implemented by NMX as a new gene-to-lead service product. It helped NMX increasing its competitivity, developing new partnerships and resulted in growth and increased revenues. The project also had positive outcomes for the partner 3 Point Bio. Indeed, the company employed the new FBLD strategies into its research program for discovering fragment hits and follow-up compounds for multiple targets. Training benefits were also numerous. Throughout the project, several students were trained and developed highly sought-after skills. At least eight of them were hired in the industry at the term of their studies.

Principal Investigator:

Steven LaPlante
INRS-Institut Armand-Frappier


Louis Vaillancourt
Sacha Larda
Patricia Bouchard

NMX Research and Solutions

Michael Serrano-Wu
3 Point Bio

Completed Project
$1,349,700 / 3 years
Supported by CQDM through:
• 3 Point Bio
• Mitacs