Starting from a series of our new 2-phenylbenzimidazole derivatives, shown to be selectively and potently active against the bovine viral diarrhea virus (BVDV), we developed a hierarchical combined experimental/molecular modeling strategy to explore the drug leads for the BVDV RNA-dependent RNA-polymerase. Accordingly, a successful 3D pharmacophore model was developed, characterized by distinct chemical features that may be responsible for the activity of the inhibitors. BVDV mutants resistant to lead compounds in our series were then isolated, and the mutant residues on the viral molecular target, the RNA-dependent RNA-polymerase, were identified. Docking procedures upon pharmacophoric constraints and mutational data were carried out, and the binding affinity of all active compounds for the RdRp were estimated. Given the excellent agreement between in silico and in vitro data, this procedure is currently being employed in the design a new series of more selective and potent BVDV inhibitors.