title: Structure based virtual screening to identify selective phosphodiesterase 4B inhibitors.
abstract: Phosphodiesterase 4 (PDE4), is a hydrolytic enzyme, is proposed as a promising target in asthma and chronic obstructive pulmonary disease. PDE4B selective inhibitors are desirable to reduce the dose limiting adverse effect associated with non-selective PDE4B inhibitors. To achieve this goal, ligand based pharmacophore modeling and molecular docking approach is employed. Pharmacophore hypotheses for PDE4B and PDE4D are generated using HypoGen algorithm. The best PDE4B pharmacophore hypothesis (Hypo1_PDE4B) consist of one hydrogen-bond acceptor and two ring aromatic features, whereas PDE4D pharmacophore hypothesis (Hypo1_PDE4D) consist of one hydrogen-bond acceptor, one hydrophobic aliphatic, and two ring aromatic features. The validated pharmacophore hypotheses are used in virtual screening to identify selective PDE4B inhibitors. The hits were screened for their estimated activity, FitValue, and quantitative estimation of drug likeness. After molecular docking analysis, ten hits were purchased for in vitro analysis. Out of these, six hits have shown potent and selective inhibitory activity against PDE4B with IC50 values ranging from 2 to 378nM.
authors: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, Mohali 160 062, Punjab, India.
authors: Rahul P
authors: RP
authors: Gangwal
authors: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, Mohali 160 062, Punjab, India.
authors: Mangesh V
authors: MV
authors: Damre
authors: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, Mohali 160 062, Punjab, India.
authors: Nihar R
authors: NR
authors: Das
authors: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, Mohali 160 062, Punjab, India.
authors: Gaurao V
authors: GV
authors: Dhoke
authors: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, Mohali 160 062, Punjab, India.
authors: Anuseema
authors: A
authors: Bhadauriya
authors: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, Mohali 160 062, Punjab, India.
authors: Rohith A
authors: RA
authors: Varikoti
authors: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, Mohali 160 062, Punjab, India.
authors: Shyam S
authors: SS
authors: Sharma
authors: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, Mohali 160 062, Punjab, India. Electronic address: abhays@niper.ac.in.
authors: Abhay T
authors: AT
authors: Sangamwar
mesh_terms: D000465:Algorithms; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010726:Phosphodiesterase Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: D010726:Phosphodiesterase Inhibitors; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4
keywords: COPD; Molecular docking; Pharmacophore; Phosphodiesterase; Virtual screening