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A combination of pharmacophore modeling, atom-based 3D-QSAR, molecular docking and molecular dynamics simulation studies on PDE4 enzyme inhibitors.
J Biomol Struct Dyn. 2016 Nov; 34(11):2481-92.JB

Abstract

Phosphodiesterases 4 enzyme is an attractive target for the design of anti-inflammatory and bronchodilator agents. In the present study, pharmacophore and atom-based 3D-QSAR studies were carried out for pyrazolopyridine and quinoline derivatives using Schrödinger suite 2014-3. A four-point pharmacophore model was developed using 74 molecules having pIC50 ranging from 10.1 to 4.5. The best four feature model consists of one hydrogen bond acceptor, two aromatic rings, and one hydrophobic group. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a high correlation coefficient (R(2)= .9949), cross validation coefficient (Q(2)= .7291), and Pearson-r (.9107) at six component partial least square factor. The external validation indicated that our QSAR model possessed high predictive power with R(2) value of .88. The generated model was further validated by enrichment studies using the decoy test. Molecular docking, free energy calculation, and molecular dynamics (MD) simulation studies have been performed to explore the putative binding modes of these ligands. A 10-ns MD simulation confirmed the docking results of both stability of the 1XMU-ligand complex and the presumed active conformation. Outcomes of the present study provide insight in designing novel molecules with better PDE4 inhibitory activity.

Authors+Show Affiliations

a Department of Pharmaceutical Chemistry , J.S.S. College of Pharmacy (Constituent College of JSS University, Mysore) , Ooty, Udhagamandalam 643001 Tamil Nadu , India.a Department of Pharmaceutical Chemistry , J.S.S. College of Pharmacy (Constituent College of JSS University, Mysore) , Ooty, Udhagamandalam 643001 Tamil Nadu , India.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26587754

Citation

Tripuraneni, Naga Srinivas, and Mohammed Afzal Azam. "A Combination of Pharmacophore Modeling, Atom-based 3D-QSAR, Molecular Docking and Molecular Dynamics Simulation Studies On PDE4 Enzyme Inhibitors." Journal of Biomolecular Structure & Dynamics, vol. 34, no. 11, 2016, pp. 2481-92.
Tripuraneni NS, Azam MA. A combination of pharmacophore modeling, atom-based 3D-QSAR, molecular docking and molecular dynamics simulation studies on PDE4 enzyme inhibitors. J Biomol Struct Dyn. 2016;34(11):2481-92.
Tripuraneni, N. S., & Azam, M. A. (2016). A combination of pharmacophore modeling, atom-based 3D-QSAR, molecular docking and molecular dynamics simulation studies on PDE4 enzyme inhibitors. Journal of Biomolecular Structure & Dynamics, 34(11), 2481-92. https://doi.org/10.1080/07391102.2015.1119732
Tripuraneni NS, Azam MA. A Combination of Pharmacophore Modeling, Atom-based 3D-QSAR, Molecular Docking and Molecular Dynamics Simulation Studies On PDE4 Enzyme Inhibitors. J Biomol Struct Dyn. 2016;34(11):2481-92. PubMed PMID: 26587754.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A combination of pharmacophore modeling, atom-based 3D-QSAR, molecular docking and molecular dynamics simulation studies on PDE4 enzyme inhibitors. AU - Tripuraneni,Naga Srinivas, AU - Azam,Mohammed Afzal, Y1 - 2016/04/12/ PY - 2015/11/21/entrez PY - 2015/11/21/pubmed PY - 2017/2/25/medline KW - docking KW - molecular dynamics KW - pharmacophore hypotheses KW - phosphodiesterases 4 KW - pyrazolopyridines SP - 2481 EP - 92 JF - Journal of biomolecular structure & dynamics JO - J Biomol Struct Dyn VL - 34 IS - 11 N2 - Phosphodiesterases 4 enzyme is an attractive target for the design of anti-inflammatory and bronchodilator agents. In the present study, pharmacophore and atom-based 3D-QSAR studies were carried out for pyrazolopyridine and quinoline derivatives using Schrödinger suite 2014-3. A four-point pharmacophore model was developed using 74 molecules having pIC50 ranging from 10.1 to 4.5. The best four feature model consists of one hydrogen bond acceptor, two aromatic rings, and one hydrophobic group. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a high correlation coefficient (R(2)= .9949), cross validation coefficient (Q(2)= .7291), and Pearson-r (.9107) at six component partial least square factor. The external validation indicated that our QSAR model possessed high predictive power with R(2) value of .88. The generated model was further validated by enrichment studies using the decoy test. Molecular docking, free energy calculation, and molecular dynamics (MD) simulation studies have been performed to explore the putative binding modes of these ligands. A 10-ns MD simulation confirmed the docking results of both stability of the 1XMU-ligand complex and the presumed active conformation. Outcomes of the present study provide insight in designing novel molecules with better PDE4 inhibitory activity. SN - 1538-0254 UR - https://www.unboundmedicine.com/medline/citation/26587754/A_combination_of_pharmacophore_modeling_atom_based_3D_QSAR_molecular_docking_and_molecular_dynamics_simulation_studies_on_PDE4_enzyme_inhibitors_ DB - PRIME DP - Unbound Medicine ER -