Improving binding mode predictions by docking into protein-specifically adapted potential fields.

The development of a protein-specifically adapted objective function for docking is described. Structural and energetic information about known protein-ligand complexes is exploited to tailor knowledge-based potentials using a "reverse", protein-based CoMFA-type (=AFMoC) approach. That way, effects due to protein flexibility and information about multiple solvation schemes can be implicitly incorporated. Compared to the application of AFMoC for binding affinity predictions, a Shannon entropy based column filtering of the descriptor matrix and the capping of adapted repulsive potentials within the binding site have turned out to be crucial for the success of this method. The new developed approach (AFMoC(obj)) was validated on a data set of 66 HIV-1 protease inhibitors, for which experimental structural information was available. Convincingly, for ligands with up to 20 rotatable bonds, in more than 75% of all cases a binding mode below 2 A rmsd has been identified on the first scoring rank when AFMoC(obj)-based potentials were used as the objective function in AutoDock. With respect to nonadapted DrugScore or AutoDock fields, the binding mode prediction accuracy was significantly improved by 14%. Noteworthy, very similar results were obtained for training and test set compounds, demonstrating the strength and robustness of this method. Implications of our findings for binding affinity predictions and its usage in virtual screening are further discussed.