High-Resolution Relaxometry for Fragment Screening.

Authors

Giulia Licciardi, Linda Cerofolini, Ulric Le Paige, Adam Kubrak, Letizia Fiorucci, Luis Padilla-Cortés, Enrico Ravera, Marco Fragai, Claudio Luchinat, Fabien Ferrage, Giacomo Parigi

Published in

Journal of medicinal chemistry. Volume 69. Issue 16. Pages 19971-19981. Aug 27, 2026.

Abstract

Characterizing weak molecular interactions remains a major challenge in drug discovery. Here, we demonstrate the power of high-resolution relaxometry (HRR), using a fast sample shuttle system, as a highly sensitive ligand-based screening method. By measuring longitudinal relaxation rates over a wide magnetic field range (2-600 MHz), we obtained site-specific Nuclear Magnetic Resonance Dispersion (NMRD) profiles for three ligands interacting with the catalytic domain of Human Matrix Metalloproteinase-12 (MMP-12). HRR unambiguously detects weak binding (KD ≈ 10-6-10-4) at protein concentrations as low as 2 μM. The analysis of the NMRD profiles provides direct, quantitative assessment of the complex dynamics, yielding a rotational correlation time in excellent agreement with the protein hydrodynamic properties. This enables discrimination between genuine protein-ligand binding and alternative processes like ligand aggregation, often observed in pan-assay interference compounds (PAINS). HRR therefore provides a robust, low-sample-consumption, physicochemical approach for fragment screening and characterization of protein-ligand complex dynamics.

PMID:
42679163
Bibliographic data and abstract were imported from PubMed on 13 Oct 2026.

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