Delineation of protein−ligand interaction modes is key for rational drug discovery. The availability of complex crystal structures is often limited by the aqueous solubility of the compounds, while lead-like compounds with micromolar affinities normally fall into the NMR intermediate exchange regime, in which severe line broadening to beyond the detection of interfacial resonances limits NMR applications. During our fragment-based lead discovery campaign against the BRM bromodomain, which recognizes the acetylated histone and closely associates with a variety of diseases, we have identified several lead-like compounds but failed to crystallize the BRM bromodomain in complex with these inhibitors. Here, we have developed two new methods to determine the 19F and 1H low-populated bound-state structural restraints of inhibitors of the BRM bromodomain using a highly skewed protein/ligand ratio. These valuable structural PCSs enriched in spatial information enabled the identification of best-fitting poses, which agree well with the crystal structure of a more soluble analog in complex with the BRM bromodomain. This approach fills the gap of the NMR structural characterization of lead-like inhibitors with moderate affinities to target proteins, which are essential for structure-guided hit-to-lead evolution towards potential epigenetic drugs.