The rapidly growing wealth of structural and functional information about kinase genes and kinase inhibitors that is fueled by a significant therapeutic role of this protein family provides a significant impetus for development of targeted computational screening approaches. In this work, we explore an ensemble-based, protein-centric approach that allows for simultaneous virtual ligand screening against multiple kinase genes and multiple kinase receptor conformations. We systematically analyze and compare the results of ligand-based and protein-centric screening approaches using both single-receptor and ensemble-based docking protocols. A panel of protein kinase targets that includes ABL, EGFR, P38, CDK2, TK, and VEGFR2 kinases is used in this comparative analysis. By applying various performance metrics we have shown that ligand-centric shape matching can provide an effective enrichment of active compounds outperforming single-receptor docking screening. However, ligand-based approaches can be highly sensitive to the choice of inhibitor queries. Employment of multiple inhibitor queries combined with parallel selection ranking criteria can improve the performance and efficiency of ligand-based virtual screening. We also demonstrated that replica-exchange Monte Carlo docking with kinome-based ensembles of multiple crystal structures can provide a superior early enrichment on the kinase targets. The central finding of this study is that incorporation of the template-based structural information about kinase inhibitors and protein kinase structures in diverse functional states can significantly enhance the overall performance and robustness of both ligand and protein-centric screening strategies. The results of this study may be useful in virtual screening of kinase inhibitors potentially offering a beneficial spectrum of therapeutic activities across multiple disease states.