Year: 2026
Type: article
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.
Source: Journal of Medicinal Chemistry
Language: English
Subfield: Spectroscopy
Field: Chemistry
Domain: Physical Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Awards: G1432992347, G3000986142, From fragments to high affinity binders interfacing integrated structural biology, medicinal chemistry and artificial intelligence, Multiscale Dynamics with Ultrafast High-Resolution Relaxometry, Multiscale Dynamics with Ultrafast High-Resolution Relaxometry, G4797496272, G5478505256, G8142830000, G972786147
OpenAlex ID: W7202295313