Pharmacophore-Based Virtual Screening and Molecular Docking Studies to Identify Selective Inhibitors of Phosphodiesterase 4B

Abstract

Background: Inhibition of phosphodiesterase 4 (PDE4) is a promising therapeutic approach for the treatment of inflammatory pulmonary disorders i.e. asthma and chronic obstructive pulmonary disease. However, the treatment with PDE4 inhibitors is not definitive due to the side effects such as nausea and vomiting which are associated with the non-selective inhibitors. Objective: To identify selective PDE4B inhibitors that are expected to be potential drug candidates for the treatment of inflammatory pulmonary disorders. Methods: A shared feature pharmacophore model for both ligand and structure-based pharmacophore models for PDE4B inhibitors was developed and used as a query in the virtual screening of Maybridge and SPECS databases. The hits were filtered based on Lipinski’s rule of five and pharmacophore fit score. Finally, the hits were docked into the active site of PDE4B and PDE4D to test their affinity and selectivity. Results: Based on the virtual screening results, nine compounds were identified as final hits, where four compounds showed the highest affinity and selectivity for PDE4B over PDE4D according to the protein-ligand interactions analysis. Conclusion: Selective PDE4B inhibitors have been identified using a combination of pharmacophore-based virtual screening and molecular docking. Those inhibitors are promising candidates for pre-clinical evaluation to justify their affinity and selectivity for PDE4B and test their anti-inflammatory activity. Key words: Asthma, Chronic obstructive pulmonary disease, Molecular docking, Phosphodiesterase 4B, Virtual screening.