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Ligand Binding Sites

Ligand Binding Sites

Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...

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Updated: Jun 19, 2026

Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions

Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions

Published on: December 1, 2020

A Fragment-Based Competitive ¹⁹F LB-NMR Platform For Hotspot-Directed Ligand Profiling.

William J McCarthy^1,2, Sherine E Thomas^3,4, Tayo Olaleye¹

¹Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK, CB2 1EW.

Angewandte Chemie (International Ed. in English)

|June 19, 2024

Summary

This summary is machine-generated.

We developed a novel screening platform using competitive 19F Ligand Based NMR (LB-NMR) to precisely quantify ligand binding at protein hotspots. This method enables efficient hotspot-directed drug discovery by mapping ligand interactions at high resolution.

Keywords:

Drug Discovery Enzymes Fluorine Fragment-based discovery NMR spectroscopy

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Area of Science:

Biochemistry
Structural Biology
Chemical Biology

Background:

Ligand binding hotspots are crucial for efficient drug design.
Current methods often lack quantitative assays for hotspot-directed ligand profiling.
Targeting hotspots maximizes ligand binding efficiency.

Purpose of the Study:

To introduce a fragment-based competitive 19F Ligand Based NMR (LB-NMR) screening platform.
To enable routine, quantitative ligand profiling focused on ligand-binding hotspots.
To demonstrate the platform's utility for hotspot-directed ligand discovery.

Main Methods:

Fragment-based screening of 960 compounds against Mycobacterium abscessus PPAT.
X-ray crystallography to identify ligand-binding hotspots.
Design and synthesis of 19F reporter molecules for each hotspot.
Competitive 19F LB-NMR assays for ligand binding profiling.

Main Results:

Identified three distinct ligand-binding hotspots on the Mabs PPAT active site.
Developed specific 19F reporters for each identified hotspot.
Competitive 19F LB-NMR accurately recapitulated binding affinities and site assignments.
Results correlated well with traditional methods like ITC and X-ray crystallography.

Conclusions:

The fragment-based competitive 19F LB-NMR platform provides quantitative, hotspot-level resolution for ligand profiling.
This platform is valuable for efficient drug discovery by focusing on key interaction sites.
The method establishes a robust approach for optimizing ligand binding at identified hotspots.