For a traditional Structure Based Drug Discovery (SBDD) approach, the ligand bound conformation is determined from x-ray or cryoEM which then sheds light on key interactions between a ligand and the protein. The structure of the ligand can then be modified to improve potency. Another impacting factor that should be considered is the conformational preferences of the ligand in the absence of protein in solution. The ligand itself could have multiple possible conformations in solution depending on the number of rotatable bonds and only the bioactive pose can fit in the binding pocket of the target protein. In order to bind to the protein of interest, the solution phase ensemble needs to rearrange to adopt the bioactive pose, which may impose entropic and/or enthalpic penalties. Based on this knowledge, the design of new ligands that favor the bioactive conformations in solution should reduce these energetic penalties and result in increased affinity for the protein.
Here we present an example of using NMR solution conformational analysis to aid drug design for the small molecule inhibitor natural killer group 2D program. The complementary information provided by this analysis in addition to the x-ray bound conformations helped rationalize the design strategy of rigidifying the ligand conformation.