Rapid Identification of Inhibitors and Prediction of Ligand Selectivity for Multiple Proteins: Application to Protein Kinases.

Rapid identification of inhibitors for a family of proteins and prediction of ligand specificity are highly desirable for structure-based drug design. However, sequentially docking ligands into each protein target with conventional single-target docking methods is too computationally expensive to achieve these two goals, especially when the number of the targets is large. In this work, we use an efficient ensemble docking algorithm for simultaneous docking of ligands against multiple protein targets. We use protein kinases, a family of proteins that are highly important for many cellular processes and for rational drug design, as an example to demonstrate the feasibility of investigating ligand selectivity with this algorithm. Specifically, 14 human protein kinases were selected. First, native docking calculations were performed to test the ability of our energy scoring function to reproduce the experimentally determined structures of the ligand-protein kinase complexes. Next, cross-docking calculations were conducted using our ensemble docking algorithm to study ligand selectivity, based on the assumption that the native target of an inhibitor should have a more negative (i.e., favorable) energy score than the non-native targets. Staurosporine and Gleevec were studied as examples of nonselective and selective binding, respectively. Virtual ligand screening was also performed against five protein kinases that have at least seven known inhibitors. Our quantitative analysis of the results showed that the ensemble algorithm can be effective on screening for inhibitors and investigating their selectivities for multiple target proteins.