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Pharmacophore modeling, 3D-QSAR and docking study of 2-phenylpyrimidine analogues as selective PDE4B inhibitors.
J Theor Biol. 2016 Apr 07; 394:117-126.JT

Abstract

Pharmacophore modeling, molecular docking, and molecular dynamics (MD) simulation studies have been performed, to explore the putative binding modes of 2-phenylpyrimidine series as PDE4B selective inhibitors. A five point pharmacophore model was developed using 87 molecules having pIC50 ranging from 8.52 to 5.07. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a high correlation coefficient (R(2)=0.918), cross validation coefficient (Q(2)=0.852), and F value (175) at 4 component PLS factor. The external validation indicated that our QSAR model possessed high predictive power (R(2)=0.70). The generated model was further validated by enrichment studies using the decoy test. To evaluate the effectiveness of docking protocol in flexible docking, we have selected crystallographic bound compound to validate our docking procedure as evident from root mean square deviation. A 10ns molecular dynamics simulation confirmed the docking results of both stability of the 1XMU-ligand complex and the presumed active conformation. Further, similar orientation was observed between the superposition of the conformations of 85 after MD simulation and best XP-docking pose; MD simulation and 3D-QSAR pose; best XP-docking and 3D-QSAR poses. Outcomes of the present study provide insight in designing novel molecules with better PDE4B selective inhibitory activity.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Tripuraneni NS
Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Ooty, Udhagamandalam 643001, Tamil Nadu, India; Constituent College of JSS University, Mysore, India.
Azam MA
Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Ooty, Udhagamandalam 643001, Tamil Nadu, India; Constituent College of JSS University, Mysore, India. Electronic address: afzal9azam@hotmail.com.

MeSH

Cyclic Nucleotide Phosphodiesterases, Type 4Least-Squares AnalysisMolecular Docking SimulationMolecular Dynamics SimulationPhosphodiesterase 4 InhibitorsPyrimidinesQuantitative Structure-Activity RelationshipReproducibility of ResultsThermodynamics

Pub Type(s)

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

Language

eng

PubMed ID

26804643

Citation

Tripuraneni, Naga Srinivas, and Mohammed Afzal Azam. "Pharmacophore Modeling, 3D-QSAR and Docking Study of 2-phenylpyrimidine Analogues as Selective PDE4B Inhibitors." Journal of Theoretical Biology, vol. 394, 2016, pp. 117-126.
Tripuraneni NS, Azam MA. Pharmacophore modeling, 3D-QSAR and docking study of 2-phenylpyrimidine analogues as selective PDE4B inhibitors. J Theor Biol. 2016;394:117-126.
Tripuraneni, N. S., & Azam, M. A. (2016). Pharmacophore modeling, 3D-QSAR and docking study of 2-phenylpyrimidine analogues as selective PDE4B inhibitors. Journal of Theoretical Biology, 394, 117-126. https://doi.org/10.1016/j.jtbi.2016.01.007
Tripuraneni NS, Azam MA. Pharmacophore Modeling, 3D-QSAR and Docking Study of 2-phenylpyrimidine Analogues as Selective PDE4B Inhibitors. J Theor Biol. 2016 Apr 7;394:117-126. PubMed PMID: 26804643.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacophore modeling, 3D-QSAR and docking study of 2-phenylpyrimidine analogues as selective PDE4B inhibitors. AU - Tripuraneni,Naga Srinivas, AU - Azam,Mohammed Afzal, Y1 - 2016/01/22/ PY - 2015/11/01/received PY - 2015/12/30/revised PY - 2016/01/04/accepted PY - 2016/1/26/entrez PY - 2016/1/26/pubmed PY - 2016/12/15/medline KW - 2-Phenylpyrimidines KW - Dynamics simulation KW - Molecular docking KW - Pharmacophore hypotheses KW - Phosphodiesterase 4B SP - 117 EP - 126 JF - Journal of theoretical biology JO - J Theor Biol VL - 394 N2 - Pharmacophore modeling, molecular docking, and molecular dynamics (MD) simulation studies have been performed, to explore the putative binding modes of 2-phenylpyrimidine series as PDE4B selective inhibitors. A five point pharmacophore model was developed using 87 molecules having pIC50 ranging from 8.52 to 5.07. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a high correlation coefficient (R(2)=0.918), cross validation coefficient (Q(2)=0.852), and F value (175) at 4 component PLS factor. The external validation indicated that our QSAR model possessed high predictive power (R(2)=0.70). The generated model was further validated by enrichment studies using the decoy test. To evaluate the effectiveness of docking protocol in flexible docking, we have selected crystallographic bound compound to validate our docking procedure as evident from root mean square deviation. A 10ns molecular dynamics simulation confirmed the docking results of both stability of the 1XMU-ligand complex and the presumed active conformation. Further, similar orientation was observed between the superposition of the conformations of 85 after MD simulation and best XP-docking pose; MD simulation and 3D-QSAR pose; best XP-docking and 3D-QSAR poses. Outcomes of the present study provide insight in designing novel molecules with better PDE4B selective inhibitory activity. SN - 1095-8541 UR - https://www.unboundmedicine.com/medline/citation/26804643/Pharmacophore_modeling_3D_QSAR_and_docking_study_of_2_phenylpyrimidine_analogues_as_selective_PDE4B_inhibitors_ DB - PRIME DP - Unbound Medicine ER -