Fragment-based lead discovery has emerged as one of the most efficient screening strategies for finding hit molecules in drug discovery. Recently, a novel strategy based on a class of fragments characterized by an ultralow molecular weight (ULMW) has been proposed. These fragments bind to the target with a very low affinity, requiring reliable biophysical methods for detection. The most notable application of ULMW used a set of 81 fragments, named MiniFrags, and screened them by X-ray crystallography. We extended the utilization of this novel class of fragments to another gold standard technique for fragment-based screening: nuclear magnetic resonance (NMR). Here, we present a novel NMR protocol to detect and analyze such weak interactions in a challenging real-world scenario: a flexible target with a flat, water-exposed binding site. We identified a subset of 69 highly water-soluble MiniFrags that were screened against the antiapoptotic protein human Bfl-1.