One of the latest trends in drug discovery screening shows a rise in the number of explorative targets. In order to evaluate these targets, the industry needs screening technologies that offer flexibility in characterizing binding events between more heterologous targets and ligands from large or new chemical spaces. Dianthus NT.23PicoDuo swiftly detects and quantifies molecular interactions in solution, independent of the molecular mass of the two interacting molecules, making it a perfect match for fragment-based screening with compounds representing a large chemical space. In this application note, we show data from single-dose screening of a fragment library with a broad molecular mass and complexity range against the target molecule histone methyltransferase (HMT) G9a, followed by affinity constant determination (Kd) for a selection of hit molecules. At the end of the study, we screened 5,784 data points including controls in less than 8 hours of instrument time, using less than 20 μg of target protein. Affinities were in the high micromolar range as expected from fragments, and in good agreement with published values for the positive control.