Molecular modelling is widely used in support of medicinal chemistry programs, with several theoretical approaches used in attempts to expedite drug discovery. In this study, three methods – molecular docking (Glide), shape similarity (ROCS), and pharmacophore modelling (Phase) – were evaluated for their ability to reproduce experimentally determined binding modes of 25 PDE4 inhibitors, identified by X-ray crystallography. Molecular docking was able to provide a good approximation (RMSD less than 2 Å) in 59% of cases, when considering the top binding pose. The pairwise comparisons, using molecular shape similarity, gave good matches in 42% of cases. Pharmacophore models were unable to predict good binding modes for a series of PDE4 inhibitors.