Medicinal Chemistry Research

, Volume 24, Issue 10, pp 3645–3659 | Cite as

Insights into the human A1 adenosine receptor from molecular dynamics simulation: structural study in the presence of lipid membrane

Original Research
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Abstract

Homology modeling, molecular docking and molecular dynamics (MD) simulation methods were used to build a reliable model for A1AR (as one of the G protein-coupled receptors—GPCRs) and to explore the structural features and binding mechanism of ligands to this receptor. A model of A1AR was built and inserted in a hydrated lipid bilayer, and 20-ns MD simulation was performed to examine the stability of the best model. In this study, RG-14718 as the best A1AR agonist and bamifylline as a selective antagonist of A1AR have been docked into the active site of the A1AR. After docking, two 20-ns MD simulation was performed on the A1AR–ligand complex to explore effects of the presence of lipid membrane in the vicinity of the A1AR–ligand complex. At the end of the MD simulation, a change in the position and orientation of the ligand in the binding site was observed. This important observation indicated that the application of MD simulation after docking of ligands is useful. Thr270, His278 and Asn70 were crucial residues for hydrogen bonds with these ligands. Phe171, Glu172, Tyr271 and Ile274 were determined to be involved in ligand–receptor binding. The results obtained are in good agreement with most of the site-directed mutagenesis data reported by others. Our results show that molecular modeling and rational drug design for adenosine targets is a possible approach.

Keywords

Homology modeling Molecular docking Molecular dynamics simulation A1AR GPCR 
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Supplementary material

44_2015_1409_MOESM1_ESM.doc (692 kb)
Supplementary material 1 (DOC 692 kb)
44_2015_1409_MOESM2_ESM.doc (64 kb)
Supplementary material 2 (DOC 64 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Mahboubeh Mansourian
    • 1
    • 2
  • Karim Mahnam
    • 3
  • Armin Madadkar-Sobhani
    • 4
    • 5
  • Afshin Fassihi
    • 2
    • 6
  • Lotfollah Saghaie
    • 2
    • 6
  1. 1.Cellular and Molecular Research CenterYasuj University of Medical SciencesYasujIran
  2. 2.Department of Medicinal Chemistry, School of Pharmacy and Isfahan Pharmaceutical Sciences Research CenterIsfahan University of Medical SciencesIsfahanIran
  3. 3.Biology Department, Faculty of ScienceShahrekord UniversityShahrekordIran
  4. 4.Life Sciences DepartmentBarcelona Supercomputing Center (BSC)BarcelonaSpain
  5. 5.Department of Bioinformatics, Institute of Biochemistry and Biophysics (IBB)University of TehranTehranIran
  6. 6.Bioinformatics Research CenterIsfahan University of Medical SciencesIsfahanIran

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