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

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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.

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Authors and Affiliations

  1. Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran

    Mahboubeh Mansourian

  2. Department of Medicinal Chemistry, School of Pharmacy and Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

    Mahboubeh Mansourian, Afshin Fassihi & Lotfollah Saghaie

  3. Biology Department, Faculty of Science, Shahrekord University, Shahrekord, Iran

    Karim Mahnam

  4. Life Sciences Department, Barcelona Supercomputing Center (BSC), 08034, Barcelona, Spain

    Armin Madadkar-Sobhani

  5. Department of Bioinformatics, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran

    Armin Madadkar-Sobhani

  6. Bioinformatics Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

    Afshin Fassihi & Lotfollah Saghaie

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  1. Mahboubeh Mansourian
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  2. Karim Mahnam
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  3. Armin Madadkar-Sobhani
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  4. Afshin Fassihi
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Correspondence to Mahboubeh Mansourian or Karim Mahnam.

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Mansourian, M., Mahnam, K., Madadkar-Sobhani, A. et al. Insights into the human A1 adenosine receptor from molecular dynamics simulation: structural study in the presence of lipid membrane. Med Chem Res 24, 3645–3659 (2015). https://doi.org/10.1007/s00044-015-1409-6

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