title: Pharmacophore modeling and virtual screening for the discovery of new type 4 cAMP phosphodiesterase (PDE4) inhibitors.
abstract: Type 4 cAMP phosphodiesterase (PDE4) inhibitors show a broad spectrum of anti-inflammatory effects in almost all kinds of inflamed cells, by an increase in cAMP levels which is a pivotal second messenger responsible for various biological processes. These inhibitors are now considered as the potential drugs for treatment of chronic inflammatory diseases. However, some recently marketed inhibitors e.g., roflumilast, have shown adverse effects such as nausea and emesis, thus restricting its use. In order to identify novel PDE4 inhibitors with improved therapeutic indexes, a highly correlating (r = 0.963930) pharmacophore model (Hypo1) was established on the basis of known PDE4 inhibitors. Validated Hypo1 was used in database screening to identify chemical with required pharmacophoric features. These compounds are further screened by using the rule of five, ADMET and molecular docking. Finally, twelve hits which showed good results with respect to following properties such as estimated activity, calculated drug-like properties and scores were proposed as potential leads to inhibit the PDE4 activity. Therefore, this study will not only assist in the development of new potent hits for PDE4 inhibitors, but also give a better understanding of their interaction with PDE4. On a wider scope, this will be helpful for the rational design of novel potent enzyme inhibitors.
authors: Department of Biomedical Engineering, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
authors: Miaomiao
authors: M
authors: Niu
authors: Fenggong
authors: F
authors: Dong
authors: Shi
authors: S
authors: Tang
authors: Guissi
authors: G
authors: Fida
authors: Jingyi
authors: J
authors: Qin
authors: Jiadan
authors: J
authors: Qiu
authors: Kangbo
authors: K
authors: Liu
authors: Weidong
authors: W
authors: Gao
authors: Yueqing
authors: Y
authors: Gu
mesh_terms: D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D008956:Models, Chemical; D062105:Molecular Docking Simulation; D058988:Phosphodiesterase 4 Inhibitors / Q000737:chemistry*
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4