Protein-ligand docking guided by ligand pharmacophore-mapping experiment by NMR.

We developed a new protein-ligand docking calculation method using experimental NMR data. Recently, we proposed a novel ligand epitope-mapping experiment, which utilizes the difference between the longitudinal relaxation rates of ligand protons with and without irradiation of target protein protons (DIRECTION epitope-mapping experiment; Y. Mizukoshi, et al., An accurate pharmacophore mapping method by NMR, submitted for publication). Although the epitope-mapping experiment is simple and rapid, the result should reflect the proximity of ligand protons to the target protein surface. However, it cannot directly provide the protein-ligand complex structure without any other structural information. While the accuracy of protein-ligand docking software is insufficient, the software can provide many candidate complex structures. In many cases, the correct complex structure is included in the set of predicted complex structures and the correct structures could be selected by applying the above experimental result of ligand epitope mapping. In the current study, we combined the protein-ligand docking software with the NMR experimental information so as to improve the prediction of the protein-ligand complex structure. Consequently, the prediction accuracy was improved by 1.3-1.9 times (from ca. 50% to ca. 70%) in a self-docking test for the simulated epitope mapping result. Moreover, this method was applied to actual NMR experiments, and it successfully reconstructed the protein-ligand complex structures.