Exploring the Role of Water Molecules in the Ligand Binding Domain of PDE4B and PDE4D: Virtual Screening Based Molecular Docking of Some Active Scaffolds

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Author(s): Priya Singh, Mitali Mishra, Shivangi Agarwal, Samaresh Sau, Arun K. Iyer*, Sushil K. Kashaw*.

Journal Name: Current Computer-Aided Drug Design

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Background: The phosphodiesterase (PDE) is a superfamily represented by four genes: PDE4A, B,C, and D which cause the hydrolysis of phosphodiester bond of cAMP to yield inactive AMP. c-AMP catalyzing enzyme is predominant in inflammatory and immunomodulatory cells. Therapy to treat Chronic Obstructive Pulmonary Disease (COPD) with the use of PDE4 inhibitors is highly envisaged.

Objective: A molecular docking experiment with large dataset of diverse scaffolds has been performed on PDE4 inhibitors to analyze the role of amino acid responsible for binding and activation of the secondary transmitters. Apart from the general docking experiment, the main focus was to discover the role of water molecules present in the ligand-binding domain.

Method: All the compounds were docked in the PDE4B and PDE4D active cavity to produce the free binding energy scores and spatial disposition/orientation of chemical groups of inhibitors around the cavity. Under uniform condition, the experiments were carried out with and without water molecules in the LBD. The exhaustive study was carried out on the Autodock 4.2 software and explored the role of water molecules present in the binding domain.

Results: In presence of water molecule, Roflumilast has more binding affinity (-8.48 Kcal/mol with PDE4B enzyme and -8.91 Kcal/mol with PDE4D enzyme) and forms two hydrogen bonds with Gln443 and Glu369 and amino acid with PDE4B and PDE4D enzymes respectively. While in absence of water molecule its binding affinity has decreased (-7.3 Kcal/mol with PDE4B enzyme and -5.17 Kcal/mol with PDE4D enzyme) as well as no H-bond interactions were observed. Similar observation was made with clinically tested molecules.

Conclusion: In protein-ligand binding interactions, appropriate selection of water molecules facilitated the ligand binding, which eventually enhances the efficiency as well as the efficacy of ligand binding.

Keywords: Chronic Obstructive Pulmonary Disease (COPD), phosphodiester , Molecular docking , PDE4B and PDE4D

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(E-pub Ahead of Print)
DOI: 10.2174/1573409914666181105153543
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