INPHARMA: an efficient NMR-based methodology for structure-based drug design

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Small molecules play a fundamental role in the regulation of the function of proteins, nucleic acids and molecular machines. The development of specific binders that selectively alter the function of only one or a few cellular targets relies on the availability of structural information for the target active site and its mode of interaction with low affinity ligands, identified for example in screening experiments. Recently we have developed a new NMR methodology, INPHARMA, which provides access to the relative binding mode of low-affinity ligands to a common target. In accordance with structure-based drug design workflows, the INPHARMA workflow currently includes selection of binding modes from a pool of computer-generated docking poses and therefore requires a structure of the apo-receptor. In this proposal we plan to make INPHARMA applicable to protein targets without a known structure. We will develop an approach that allows direct access to the structure of the receptor/ligand complex at the binding site, with both the shape of the binding pocket and the ligand binding-mode being defined by the INPHARMA data. This will possibly transform the way SBDD is conducted by releasing the need for structural data on the receptor.