Multiple Pharmacophore Models Combined with Molecular Docking: A Reliable Way for Efficiently Identifying Novel PDE4 Inhibitors with High Structural Diversity

Zhi Chen, Guanghui Tian, Zhen Wang, Hualiang Jiang, Jingshan Shen, and Weiliang Zhu

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.