STEVEN LAPLANTE

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.

Expected Achievements/Impact: New NMR strategies are being developed to screen well-curated fragment libraries. NMR technologies are also helping to better triage hits and identify weak binders that are selective for target proteins. They are also serving to rank-order binders according to relative affinity. This effectively enables medicinal chemists to establish SAR which is an essential tool in drug design. Currently, these technologies are being tested on model targets, and once completed, will serve as general and rapid methods for identifying leads for a wide variety of drug discovery campaigns.

This project is a prime example of how CQDM’s collaborative model enables the translation of academic research for discovering the seeds for new drugs.

Principal Investigator:

Steven LaPlante
INRS-Institut Armand-Frappier

Co-investigators

Louis Vaillancourt
Sacha Larda
Patricia Bouchard

NMX Research and Solutions

Michael Serrano-Wu
3 Point Bio

Ongoing Project
$1,349,700 / 3 years
Supported by CQDM through:
• NMX
• 3 Point Bio
• INRS
• Mitacs
• MESI