Homology Modelling and Docking Studies of Human α2-Adrenergic Receptor Subtypes

Abstract

Abstractα2-adrenergic receptors play a key role in the regulation of sympathetic system, neurotransmitter release, blood pressure and intraocular pressure. Although α2-adrenergic receptors mediate a number of physiological functions in vivo and have great therapeutic potential, the absence of crystal structure of α2-adrenergic receptor subtypes is a major hindrance in the drug design efforts. The therapeutic efficacy of the available drugs is not selective for subtype specificity (α2a, α2b and α2c) leading to unwanted side effects. We used Homology modelling and docking studies to understand and analyze the residues important for agonist and antagonist binding. We have also analyzed binding site volume, and the residue variations which may play important role in ligand binding. We have identified residues through our modelling and docking studies, which would be critical in giving subtype specificity and may help in the development of future subtype-selective drugs. Homology Modelling and Docking Studies of Human a2-Adrenergic Receptor SubtypesArchana Jayaraman, Kaiser Jamil and Kavita K Kakarala* [43]. Recently, the modelling groups have used β2-adrenergic receptor as a template to model subtypes of α-adrenergic receptors, as it shares higher sequence identity (29-31%) and higher transmembrane identity (37-43%) with α2-ARs [44][45][46].The structure of the Human Dopamine D3 receptor was available very recently [31]. We have modelled α2-ARs using Human Dopamine D3 receptor in complex with a D2/D3 selective antagonist (PDB ID: 3PBL) as template structure. The sequence identity and transmembrane identity of Human dopamine D3 receptor (α2a: 34%,49% ; α2b: 32%,49%; α2c: 34%,49%) was higher than β2-adrenergic receptor (PDB ID: 2RH1) (α2a: 31%, 42% ; α2b: 28%,41%; α2c: 29%,42%), Human Histamine H1 receptor complexed with doxepin (PDB ID: 3RZE), M3 muscarinic acetylcholine receptor (PDB ID: 4DAJ), Mu-opioid receptor (PDB ID: 4DKL), a lipid G protein-coupled receptor (PDB ID: 3V2W), M2 muscarinic receptor bound to antagonist 3-quinuclidinyl-benzilate (PDB ID: 3UON), Kappa opioid in complex with JDTic (PDB ID: 4DJH), 5-hydroxytryptamine 1b in complex with dihydroergotamine (PDB ID: 4IAQ), 5-hydroxytryptamine 2b in complex with ergotamine (PDB ID: 4IB4), Delta opioid bound to naltrindole (PDB ID: 4EJ4), Neurotensin receptor 1 in complex with neurotensin (PDB ID: 4GRV), chemokine CXCR1 in phospholipid bilayers (PDB ID: 2LNL) and Protease activated receptor 1 bound with antagonist vorapaxar (PDB ID: 3VW7) ( Table 1). The models of α2-ARs namely α2-a, α2-b, α2-c were minimized and checked for stereochemical correctness then docked with ligands reported to interact with alpha adrenergic receptors using Glide. As the available models of α2a-, α2b-and α2c-ARs was based on either rhodopsin or β-adrenergic receptor, we suggest that the model based on Dopamine may prove better than rhodopsin/ beta adrenergic based model in predicting residues important for subtype specificity, as it shares more sequence identity in the transmembr...

Structure and dynamics of DRD4 bound to an agonist and an antagonist usingin silicoapproaches

“…In our simulations, the hydroxyl groups of dopamine were found to maintain their H‐bond interactions with residues Ser196 5.42 and Ser200 5.46 whereas spiperone formed H‐bonds with Asp115 3.32 and His366 6.55 . In our dopamine‐bound DRD4 simulations, the para‐hydroxyl of the catechol moiety interacts with Ser196 5.42 (Occupancy: 77.39%) and the meta‐hydroxyl interacts with Ser200 5.46 (Occupancy: 70.16%) as also seen in previous studies . However, it appears that the interaction of OH groups of catechol moiety with Ser196 5.42 and Ser200 5.46 is highly dynamic.…”

Identifying binding modes of two synthetic derivatives of adrenalin to the α2C-adrenoceptor by using molecular modeling; insights into the α2C–adrenoceptor activation

“…The accuracy of homology model is exclusively reliant on the template and could be increases by the multiple sequence comparison and alignment. Several homology models of  subtype of adrenoceptors have been developed based on the crystal structure of bovine rhodopsin [11], human dopamine D3 receptor [12] and β2-adrenergic receptor [13][14][15] so far. However, in all the resulted models the sequence identity of the target-template did not exceeded than the 30%.…”

“Molecular Modeling and Identification of Inhibitors against Human Mitochondrial Thymidine Kinase 2”

“…The file name, without the grd extension, is displayed in the Receptor grid base name text box. We can also enter the base name directly into the text box [16].…”