title: Identifying binding modes of two synthetic derivatives of adrenalin to the α2C-adrenoceptor by using molecular modeling; insights into the α2C-adrenoceptor activation.
abstract: Although, α2C adrenergic receptor (AR) mediates a number of physiological functions in vivo and has great therapeutic potential, the absence of its crystal structure is a major difficulty in the activation mechanism studies and drug design endeavors. Here, a homology model of α2C AR has been presented by means of multiple sequence alignment. The used templates were the latest crystal structures of the other ARs (Protein Data Bank IDs: 2R4R, 2RH1, 4GPO, 3P0G, 4BVN and 4LDO) that have 38.4% identity with the query. We then conducted docking simulations to understand and analyze the binding of noradrenaline (NOR), and its derivatives, namely arachidonoyl adrenalin (AA-AD) and arachidonoyl noradrenalin (AA-NOR) to the receptor. The existence of H-bonds between the ligands and SER218 residue implies the same binding site of derivatives with respect to the NOR. AA-AD and AA-NOR bind to the receptor with the larger binding affinities. The presence of salt bridge between ARG149 and GLU377 in the free receptor, obtained from molecular dynamics studies proved that the receptor still is in its basal state before binding process take places. The activation process is characterized by increasing in the RMSD values of the backbone receptor in the bound state, increasing the RMSF of the transmembrane involved in the activation process and the disappearance of the ARG149-GLU377 salt bridge.
authors.affiliation: Department of Chemistry, University of Isfahan, Isfahan 81746-73441, Iran.
authors.forename: Samira
authors.initials: S
authors.lastname: Gholami
authors.affiliation: Department of Chemistry, University of Isfahan, Isfahan 81746-73441, Iran. Electronic address: bordbar@chem.ui.ac.ir.
authors.forename: A Khalegh
authors.initials: AK
authors.lastname: Bordbar
authors.affiliation: Department of Physics, University of Isfahan, Isfahan 81746-73441, Iran.
authors.forename: Amir
authors.initials: A
authors.lastname: Lohrasebi
mesh_terms: D016718:Arachidonic Acid; D001665:Binding Sites; D030562:Databases, Protein; D004837:Epinephrine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009638:Norepinephrine / Q000031:analogs & derivatives* / Q000378:metabolism; D011485:Protein Binding; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D016415:Sequence Alignment; D040681:Structural Homology, Protein
chemical_list: D018341:Receptors, Adrenergic, alpha-2; D016718:Arachidonic Acid; D009638:Norepinephrine; D004837:Epinephrine
keywords: Adrenergic receptors; Arachidonoyl adrenalin; Arachidonoyl noradrenalin; Homology modeling; Molecular docking; Molecular dynamics simulation