Identification of selective inhibitors of phosphodiesterase 4B using pharmacophore-based virtual screening and molecular docking approaches
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1
Faculty of Pharmaceutical Sciences, UCSI University, Malaysia
Background
Phosphodiesterase 4B (PDE4B) catalyzes the inactivation of cyclic adenosine monophosphate (cAMP) which is a pivotal second messenger responsible for various biological processes. This enzyme is expressed in immune, inflammatory, and airway smooth muscle cells, thus its inhibition is considered as a treatment option for inflammatory pulmonary disorders i.e. asthma and chronic obstructive pulmonary disease. In contrast to PDE4B, PDE4D is expressed in the area postrema and nucleus of the solitary tract, which are responsible for the emetic response. In this regard, a PDE4B inhibitor selective over PDE4D is expected to be useful anti-inflammatory agent.
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 virtual screening of two libraries to identify novel scaffolds that selectively inhibit PDE4B. The hit compounds were filtered according to Lipinski’s rule of five and pharmacophore fit score. Finally, the molecular docking study was applied to evaluate the affinity and selectivity of the hit compounds to PDE4B over PDE4D.
Results
The resulted shared feature pharmacophore model consists of three features: a hydrogen bond acceptor, a hydrophobic unit, and an aromatic ring. The pharmacophore model was used in the virtual screening of Maybridge and SPECS databases. The hit compounds were filtered based on Lipinski’s rule of five and pharmacophore fit score higher than 38.90. Nine compounds were identified as final hits, where four compounds showed higher affinity to PDE4B over PDE4D in molecular docking.
Conclusion
In this study, four selective PDE4B inhibitors were identified using a combination of ligand-based virtual screening and molecular docking. These inhibitors can be further evaluated for their PDE4B inhibition activity in vitro and anti-inflammatory effect in vivo.
Acknowledgements
This research was funded by the Centre of Excellence for Research, Value Innovation and Entrepreneurship(CERVIE), UCSI University, Malaysia.
Keywords:
Phosphodiesterase 4B,
Asthma,
Chronic obstructive pulmonary disease, COPD,
Pharmacophore,
Docking
Conference:
International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18)
“Seizing Opportunities and Addressing Challenges of Precision Medicine”, Putrajaya, Malaysia, 3 Dec - 5 Feb, 2019.
Presentation Type:
Oral Presentation
Topic:
Inflammatory diseases
Citation:
Al-Nema
M and
Gaurav
A
(2019). Identification of selective inhibitors of phosphodiesterase 4B using pharmacophore-based virtual screening and molecular docking approaches.
Front. Pharmacol.
Conference Abstract:
International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18)
“Seizing Opportunities and Addressing Challenges of Precision Medicine”.
doi: 10.3389/conf.fphar.2018.63.00113
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Received:
30 Sep 2018;
Published Online:
17 Jan 2019.
*
Correspondence:
Dr. Anand Gaurav, Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia, anand.pharma@gmail.com