A Comprehensive ¹⁹F NMR Framework for Fragment-Based Drug Discovery: The Validated Screening Library OpenFL600 and...

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Biophysics

Background:

• Small-molecule drug discovery requires identifying and optimizing initial chemical starting points (screening hits).
• Fragment-based drug discovery (FBDD) using fluorine-19 NMR screening is a sensitive method for hit identification.
• A need exists for robust, non-proprietary screening libraries and efficient methods for hit prioritization.

Purpose of the Study:

• To design and validate a non-proprietary fluorine-19 NMR screening library (OpenFL600) for diverse target classes.
• To demonstrate the library's utility in identifying specific hits and enabling structure-activity relationship (SAR) studies.
• To present a streamlined workflow for hit-to-lead progression using chemical shift anisotropy (CSA) Affinity Ranking (CSAR).

Main Methods:

• Design and quality control of the OpenFL600 library comprising diverse fragments.
• Application of fluorine-19 NMR screening campaigns against various targets including RNA, GPCRs, kinases, protein-protein interactions, and proteases.
• Utilizing chemical shift anisotropy (CSA) Affinity Ranking (CSAR) for rapid affinity assessment of identified hits.

Main Results:

• The OpenFL600 library successfully identified specific hits for 11 diverse targets, yielding valuable SAR data.
• Absence of promiscuous binders confirmed the high quality and specificity of the OpenFL600 library.
• CSAR enabled efficient affinity ranking, significantly streamlining the prioritization of screening hits.

Conclusions:

• The OpenFL600 library provides a comprehensive framework for fluorine-19 NMR-based screening across multiple target classes.
• The library facilitates assessment of target druggability and enables efficient hit-to-lead progression.
• This integrated approach enhances the efficiency of small-molecule drug discovery.