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Structure based virtual screening to identify selective phosphodiesterase 4B inhibitors.
J Mol Graph Model. 2015 Apr; 57:89-98.JM

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.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Gangwal RP
Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, Mohali 160 062, Punjab, India.
Damre MV
Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, Mohali 160 062, Punjab, India.
Das NR
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, Mohali 160 062, Punjab, India.
Dhoke GV
Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, Mohali 160 062, Punjab, India.
Bhadauriya A
Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, Mohali 160 062, Punjab, India.
Varikoti RA
Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, Mohali 160 062, Punjab, India.
Sharma SS
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, Mohali 160 062, Punjab, India.
Sangamwar AT
Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, Mohali 160 062, Punjab, India. Electronic address: abhays@niper.ac.in.

MeSH

AlgorithmsCyclic Nucleotide Phosphodiesterases, Type 4Drug Evaluation, PreclinicalHumansInhibitory Concentration 50Models, MolecularMolecular Docking SimulationPhosphodiesterase InhibitorsReproducibility of ResultsStructure-Activity RelationshipUser-Computer Interface

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25687765

Citation

Gangwal, Rahul P., et al. "Structure Based Virtual Screening to Identify Selective Phosphodiesterase 4B Inhibitors." Journal of Molecular Graphics & Modelling, vol. 57, 2015, pp. 89-98.
Gangwal RP, Damre MV, Das NR, et al. Structure based virtual screening to identify selective phosphodiesterase 4B inhibitors. J Mol Graph Model. 2015;57:89-98.
Gangwal, R. P., Damre, M. V., Das, N. R., Dhoke, G. V., Bhadauriya, A., Varikoti, R. A., Sharma, S. S., & Sangamwar, A. T. (2015). Structure based virtual screening to identify selective phosphodiesterase 4B inhibitors. Journal of Molecular Graphics & Modelling, 57, 89-98. https://doi.org/10.1016/j.jmgm.2015.01.007
Gangwal RP, et al. Structure Based Virtual Screening to Identify Selective Phosphodiesterase 4B Inhibitors. J Mol Graph Model. 2015;57:89-98. PubMed PMID: 25687765.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structure based virtual screening to identify selective phosphodiesterase 4B inhibitors. AU - Gangwal,Rahul P, AU - Damre,Mangesh V, AU - Das,Nihar R, AU - Dhoke,Gaurao V, AU - Bhadauriya,Anuseema, AU - Varikoti,Rohith A, AU - Sharma,Shyam S, AU - Sangamwar,Abhay T, Y1 - 2015/01/22/ PY - 2014/07/10/received PY - 2014/12/30/revised PY - 2015/01/14/accepted PY - 2015/2/18/entrez PY - 2015/2/18/pubmed PY - 2015/12/17/medline KW - COPD KW - Molecular docking KW - Pharmacophore KW - Phosphodiesterase KW - Virtual screening SP - 89 EP - 98 JF - Journal of molecular graphics & modelling JO - J Mol Graph Model VL - 57 N2 - 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. SN - 1873-4243 UR - https://www.unboundmedicine.com/medline/citation/25687765/Structure_based_virtual_screening_to_identify_selective_phosphodiesterase_4B_inhibitors_ DB - PRIME DP - Unbound Medicine ER -