In the study of small molecule ligands and candidate macromolecular targets, water spins in long-lived association with macromolecules (proteins or nanoparticles) constitute a remarkable source of magneti-zation that can be exploited to reveal ligand-target binding. In this work we show how the selective sat-uration of water spins complemented with adiabatic off-resonance spin-locks can remove the NOE contribution of bulk water in the final difference spectrum, leading to uniformly enhanced signals that reveal weak ligand-target interactions.(c) 2022 Elsevier Inc. All rights reserved.