Discover natural compounds as potential phosphodiesterase-4B inhibitors via computational approaches

Abstract

cAMP, intracellular cyclic adenosine monophosphate, is a ubiquitous second messenger that plays a key role in many physiological processes. PDE4B which can reduce the cAMP level by hydrolyzing cAMP to 5'-AMP has become a therapeutic target for the treatment of human diseases such as respiratory disorders, inflammation diseases, neurological and psychiatric disorders. However, the use of currently available PDE4B inhibitors is restricted due to serious side effects caused by targeting PDE4D. Hence, we are attempting to find out subfamily-selective PDE4B inhibitors from natural products, using computer-aided approaches such as virtual screening, docking, and molecular dynamics simulation. Finally, four potential PDE4B-selective inhibitors (ZINC67912770, ZINC67912780, ZINC72320169, and ZINC28882432) were found. Compared to the reference drug (roflumilast), they scored better during the virtual screening process. Binding free energy for them was -317.51, -239.44, -215.52, and -165.77 kJ/mol, better than -129.05 kJ/mol of roflumilast. The pharmacophore model of the four candidate inhibitors comprised six features, including one hydrogen bond donor, four hydrogen bond acceptors, and one aromatic ring feature. It is expected that our study will pave the way for the design of potent PDE4B-selective inhibitors of new drugs to treat a wide variety of diseases such as asthma, COPD, psoriasis, depression, etc.

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

“…While region HID199-ARG229 became more flexible due to the absence of interactions. These results are consistent with previous studies and postulate that the region ASN253-ILE299 is favourable for binding and region LEU249-ILE299 is involved in hydrophobic interactions ( Li et al., 2016 ; Tripuraneni and Azam, 2016 ; Xu et al., 2000 ). In contrast to HTS04529 and HTS05856, only hydrophobic and hydrogen-bonding interactions were observed between rolipram and PDE4B.…”

“…Thus to overcome these problems, a selective PDE4B inhibitor may offer a solution for maximising the therapeutic action and minimising the side effects ( Fan Chung, 2006 ; Wang et al., 1999 ). Recently, the implication of pharmacophore modelling, molecular docking and molecular dynamics (MD) simulations in the discovery of subfamily-selective PDE4B inhibitors showed a lot of success ( Li et al., 2016 ; Shubina et al., 2015 ). Accordingly, pharmacophore-based virtual screening, molecular docking and MD simulations have been applied in this study with the objective to identify a selective PDE4B inhibitor and unravel the crucial amino acids involved in the binding interactions with the inhibitor and its stabilisation in the active site of PDE4B.…”

Discovery of 2‐(3,4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl)acetonitriles as phosphodiesterase 4 inhibitors with anti‐neuroinflammation potential based on three‐dimensional quantitative structure–activity relationship study

“…Despite numerous 3D-QSAR studies on PDE4 inhibitors with deferent structure types having been published (Gratteri, Bonaccini The actual IC 50 against human PDE4 catalytic domains (PDE4CAT) were obtained from our reported references (Zhou et al, 2015 Marella et al, 2013;Xiong, Lu, Li, Yang, & Zhan, 2006;Zheng et al, 2008), the application of 3D-QSAR study in the design and development of new PDE4 inhibitors is still scarce. Recently, pharmacophore modeling of 3D-QSAR was successfully used in the discovery of selective PDE4 inhibitor (Li et al, 2016). Hence, the goal of this study was to further definitively characterize the binding modes of catecholic PDE4 inhibitors, which will be used in the design of new PDE4 inhibitors.…”

Discovery of a Potential HER2 Inhibitor from Natural Products for the Treatment of HER2-Positive Breast Cancer

“…The Vina score was calculated by AutoDock Vina program. The detailed parameters refer to our previous studies [ 38 , 39 , 40 , 41 ].…”