Structural determinants of the alpha2 adrenoceptor subtype selectivity

Halip, Liliana; Curpăn, Ramona; Mracec, Mircea; Bologa, Cristian

doi:10.1016/j.jmgm.2011.04.011

Cited by 19 publications

(33 citation statements)

References 42 publications

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“…Most of the residue, that were predicted facing the ligand binding cavity by earlier investigators, based on bovine Rhodopsin [22,25] and β2-adrenergic receptor [44][45][46][47] models, were occupying the same position in the models based on human D3 Dopamine receptor also. The amino acid residues predicted to be the key determinants of agonist binding, D3.32, W6.48, S5.43 and S5.46, were well positioned to interact with the protonated nitrogen, aromatic ring, and catecholic hydroxyls of catecholamine agonists (Figure 3).…”

Section: The Orientation Of Common Residues In the Models And The Prementioning

confidence: 89%

“…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].…”

Section: Homology Modelling and Docking Studies Of Human A2-adrenergimentioning

confidence: 99%

“…These ligands have been reported by the research studies to bind to and interact with the α2-AR. A set of eight agonists including endogenous ligands such as Dopamine, Adrenaline, known α2 agonists such as Clonidine, Dexmedetomidine and subtype selective agonist Guanfacine were selected from literature for docking studies [23,39,45]. Sixteen antagonists including subtype specific ligands such as BRL-44408, JP-1302, OPC-2836 and others such as ARC239, Clozapine, WB4101 that have been reported to bind to α2 adrenergic receptors were chosen for the docking studies to analyse their interactions with the α2-AR models based on Dopamine receptor (PDB ID:3PBL) [22,46,52].…”

Section: Ligand Selectionmentioning

confidence: 99%

“…The transmembrane regions were aligned according to Baldwin's model for the alpha carbon positions in the transmembrane helices of the GPCR family [55]. In all three α2-ARs, the N, C-terminal part and the third intracellular loop (IL3), which is over 100 residues long, were not modelled because the available loop modelling algorithms are limited to up to 13 residues long loops [45].…”

Section: Homology Modellingmentioning

confidence: 99%

“…This was followed by the availability of other members of GPCR family, Human β2-adrenergic receptor [26], turkey β1-adrenergic receptor [27], squid Rhodopsin [28], Human adenosine A2a receptor [29], chemokine CXCR4 [30], Human Dopamine D3 receptor in complex with a D2/ D3 selective antagonist Eticlopride [31], and most recently histamine H1 (H1R) [32], M3 muscarinic acetylcholine receptor [33], Mu-opioid receptor [34], a lipid G protein-coupled receptor [35], M2 muscarinic receptor [36], Kappa opioid [37], Delta opioid [38], Neurotensin receptor 1 [39], chemokine CXCR1 [40], Protease activated receptor 1 [41], 5-hydroxytryptamine 1b [42], and 5-hydroxytryptamine 2b [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].…”

Section: Introductionmentioning

confidence: 99%

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

Jayaraman¹,

Jamil²,

Kakarala³

2015

J Comput Sci Syst Biol

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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...

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Section: The Orientation Of Common Residues In the Models And The Prementioning

confidence: 89%

Section: Homology Modelling and Docking Studies Of Human A2-adrenergimentioning

confidence: 99%

Section: Ligand Selectionmentioning

confidence: 99%

Section: Homology Modellingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Jayaraman¹,

Jamil²,

Kakarala³

2015

J Comput Sci Syst Biol

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The Noradrenergic System

2019

Chemical Biology of Neurodegeneration

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Computer-Aided Drug Design Approaches to Study Key Therapeutic Targets in Alzheimer’s Disease

et al. 2017

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Parkinson's Disease (PD) is a long-term neurodegenative brain disorder that mainly affects the motor system. The causes are still unknown, and even though currently there is no cure, several therapeutic options are available to manage its symptoms. The development of novel anti-parkinsonian agents and an understanding of their proper and optimal use are, indeed, highly demanding. For the last decades, L-3,4-DihydrOxyPhenylAlanine or levodopa (L-DOPA) has been the gold-standard therapy for the symptomatic treatment of motor dysfunctions associated to PD. However, the development of dyskinesias and motor fluctuations (wearing-off and on-off phenomena) associated to long-term L-DOPA replacement therapy have limited its antiparkinsonian efficacy. The investigation for non-dopaminergic therapies has been largely explored as an attempt to counteract the motor side effects associated to dopamine replacement therapy. Being one of the largest cell membrane protein families, G-Protein-Coupled Receptors (GPCRs) have become a relevant target for drug discovery focused in a wide range of therapeutic areas, including Central Nervous System (CNS) diseases. The modulation of specific GPCRs potentially implicated in PD, excluding dopamine receptors, may provide promising non-dopaminergic therapeutic alternatives for symptomatic treatment of PD. In this review, we focused on the impact of specific GPCR subclasses, including dopamine receptors, adenosine receptors, muscarinic acetylcholine receptors, metabotropic glutamate receptors, and 5-hydroxytryptamine receptors, on the pathophysiology of PD and the importance of structure-and ligand-based in silico approaches for the development of small molecules to target these receptors.

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Structural determinants of the alpha2 adrenoceptor subtype selectivity

Cited by 19 publications

References 42 publications

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

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

The Noradrenergic System

Computer-Aided Drug Design Approaches to Study Key Therapeutic Targets in Alzheimer’s Disease

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