A flexible-receptor docking protocol was designed for treating binding-site side-chain flexibility by integrating essential aspects of "Conformational Selection" and "Induced Fit" in a hierarchical fashion. Assessed in a diverse set of pharmaceutically relevant targets, this protocol showed improved performance in reproducing binding poses and ligand enrichment studies compared to rigid-receptor docking. Moreover, it has also exhibited encouraging efficiency in prospective ligand discovery for Pim-1 kinase, which led to novel Pim-1 inhibitors with single-digit nanomolar potencies.