Abstract: | In early drug discovery approaches, screening hits are often weak affinity binders that are difficult to characterize in structural detail, particularly towards obtaining the 3D structure of protein–ligand complexes at atomic resolution. NMR is the outstanding technique to tackle such problems, yet suffers from a tedious structure calculation process. N MR2 was recently developed to alleviate the laborious element of routine NMR structure calculation procedures and provides the structural information at protein–ligand interaction sites orders of magnitude faster than standard procedures. The N MR2 method was extended to weak binders and applied to the oncoproteins HDM2 and MDMX. The structure of the MDMX‐SJ212 complex is reported with a K d of approximately 0.7 μm ; the complex structure of HDM2 with the mm affinity ligand #845 exhibits a new scaffold. |