Docking based screening and molecular dynamics simulations to identify potential selective PDE4B inhibitor

• Main Authors: Mayasah Al-Nema, Anand Gaurav, Vannajan Sanghiran Lee
• Format: Article
• Language: English
• Published: Elsevier 2020-09-01
• Series: Heliyon
• Subjects: Phosphodiesterase 4; Shared feature pharmacophore model; Virtual screening; Molecular docking; Molecular dynamics simulations; Computational chemistry
• Online Access: http://www.sciencedirect.com/science/article/pii/S2405844020316996

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 non-selective PDE4 inhibitors is associated with side effects such as nausea and vomiting. Among the subtypes of PDE4 inhibited by these inhibitors, PDE4B is expressed in immune, inflammatory and airway smooth muscle cells, whereas, PDE4D is expressed in the area postrema and nucleus of the solitary tract. Thus, PDE4D inhibition is responsible for the emetic response. In this regard, a selective PDE4B inhibitor is expected to be a potential drug candidate for the treatment of inflammatory pulmonary disorders. Therefore, a shared feature pharmacophore model was developed and used as a query for the virtual screening of Maybridge and SPECS databases. A number of filters were applied to ensure only compounds with drug-like properties were selected. Accordingly, nine compounds have been identified as final hits, where HTS04529 showed the highest affinity and selectivity for PDE4B over PDE4D in molecular docking. The docked complexes of HTS04529 with PDE4B and PDE4D were subjected to molecular dynamics simulations for 100ns to assess their binding stability. The results showed that HTS04529 was bound tightly to PDE4B and formed a more stable complex with it than with PDE4D.