Multiple pharmacophore models were constructed based on the 18 crystal structures of phosphodiesterase 4 (PDE4) in complex with different inhibitors for discovering new potential PDE4 inhibitors. After validation of their efficiency in screening, 10 of the pharmacophore models were confirmed effective. Remarkably, the hits retrieved by these effective pharmacophore models were different, demonstrating that different pharmacophore models may have different performances in database screening. Therefore, all these models were employed to screen the compound database SPECS for finding potent leads with much structural diversity. Combining all the screened hits based on the 10 pharmacophore models, followed by molecular docking and bioassay, 4 of 53 tested compounds were found as active as rolipram (a well studied PDE4 inhibitor). More impressively, the four potent inhibitors with different chemical scaffolds were discovered by three different pharmacophore models separately, suggesting that a single pharmacophore model-based screening might not be efficient in thoroughly identifying potential hits from a compound database. This study also revealed that ligand-receptor complex structure-based pharmacophore is more efficient for identifying potent hits with great structural diversity in comparison with ligand-based pharmacophore and similarity search approaches. Therefore, multiple pharmacophore model-based virtual screenings should be used, if available, in combination with molecular docking for fully discovering hit compounds from compound databases.