Understanding of Protein-Ligand Interactions with INPHARMA

The major impediment in application of structure based drug design is insufficient information about interaction between small molecule and its target protein. Although crystallographic and protein based NMR methods provide superb input to the protein – ligand interaction, the inability to obtain crystals for many proteins of interest in parallel with a 50 kDa cut off for standard NMR techniques, highlights a need for alternative techniques. The newly established INPHARMA (Interligand NOEs for Pharmacophore Mapping) method fills this gap. The INPHARMA enables pharmacophore mapping by means of NOE transfer from one ligand to another via protein protons in their common binding site. The presence of INPHARMA between two compounds is indicative of their relative orientation, and if the binding site of one of them is known, information on the binding modes of both compounds can be obtained.

In this study we applied the INPHRAMA method to a group of kinase ligands. The acquisition of competition STD experiments indicated interaction of all compounds with the same binding site, while analysis of INPHARMA correlations enabled establishment of a common pharmacophore. The identified pharmacophore will be used to screen libraries of natural products and synthetic compounds to select new kinase inhibitors.