title: 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.
authors.affiliation: a College of Life Sciences & Key Laboratory for Bio-resources of Ministry of Education , Sichuan University , Chengdu 610064 , China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: a College of Life Sciences & Key Laboratory for Bio-resources of Ministry of Education , Sichuan University , Chengdu 610064 , China.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhou
authors.affiliation: a College of Life Sciences & Key Laboratory for Bio-resources of Ministry of Education , Sichuan University , Chengdu 610064 , China.
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.affiliation: a College of Life Sciences & Key Laboratory for Bio-resources of Ministry of Education , Sichuan University , Chengdu 610064 , China.
authors.forename: Jianzong
authors.initials: J
authors.lastname: Li
authors.affiliation: a College of Life Sciences & Key Laboratory for Bio-resources of Ministry of Education , Sichuan University , Chengdu 610064 , China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Feng
authors.affiliation: a College of Life Sciences & Key Laboratory for Bio-resources of Ministry of Education , Sichuan University , Chengdu 610064 , China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Wang
authors.affiliation: a College of Life Sciences & Key Laboratory for Bio-resources of Ministry of Education , Sichuan University , Chengdu 610064 , China.
authors.forename: Chuanfang
authors.initials: C
authors.lastname: Wu
authors.affiliation: a College of Life Sciences & Key Laboratory for Bio-resources of Ministry of Education , Sichuan University , Chengdu 610064 , China.|b State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital , Sichuan University , Chengdu 610041 , China.|c State Key Laboratory of Oral Diseases , West China College of Stomatology, Sichuan University , Chengdu 610041 , China.
authors.forename: Jinku
authors.initials: J
authors.lastname: Bao
mesh_terms: D001665:Binding Sites; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry*; D055808:Drug Discovery; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D058988:Phosphodiesterase 4 Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding
chemical_list: D001688:Biological Products; D058988:Phosphodiesterase 4 Inhibitors; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4
keywords: cAMP; drug development; in silico; inhibitor; phosphodiesterase-4B