Model structures of α-2 adrenoceptors in complex with automatically docked antagonist ligands raise the possibility of interactions dissimilar from agonist ligands

Xhaard, Henri; Nyrönen, Tommi; Rantanen, Ville-Veikko; Ruuskanen, Jori O.; Laurila, Jonne M.; Salminen, Tiina A.; Scheinin, Mika; Johnson, Mark S.

doi:10.1016/j.jsb.2004.12.008

Cited by 27 publications

(71 citation statements)

References 51 publications

(86 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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: 90%

“…Twenty four ligands (agonist (Figure 1) and antagonist ( Figure 2)), were selected from the literature [22,46,52,53]. These ligands have been reported by the research studies to bind to and interact with the α2-AR.…”

Section: Ligand Selectionmentioning

confidence: 99%

“…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]. The 3D structures were obtained from small molecule database Pubchem, present in NCBI server (http://pubchem.ncbi.nlm.nih.gov/).…”

Section: Ligand Selectionmentioning

confidence: 99%

“…Later on, it was Bovine rhodopsin and for many years bovine Rhodopsin has been the only GPCR with experimental structural information available, and all the homology modelling efforts were focused on this structure [16,17]. Homology modelling and docking studies were earlier based on bovine Rhodopsin even though it showed lower sequence identity (21%) and lower transmembrane identity (26%) as the availability of high resolution GPCR structures was the limitation [18][19][20][21][22][23][24][25]. 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].…”

Section: Introductionmentioning

confidence: 99%

“…The analysis measures are both global and site-and specific. Ballesteros-Weinstein convention was used to assign residue positions throughout our analysis for transmembrane helices [50] as well as loop regions [22]. …”

mentioning

confidence: 99%

See 4 more Smart Citations

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

Jayaraman¹,

Jamil²,

Kakarala³

2015

J Comput Sci Syst Biol

View full text Add to dashboard Cite

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...

show abstract

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

confidence: 90%

Section: Ligand Selectionmentioning

confidence: 99%

Section: Ligand Selectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

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

View full text Add to dashboard Cite

show abstract

Synthesis, biological evaluation, and molecular modeling of ORM‐10921 and its analogs as α_2C‐adrenoceptor antagonists

Zhu

Zhang

et al. 2023

Archiv der Pharmazie

View full text Add to dashboard Cite

The α 2C -adrenoceptor (α 2C -AR) is regarded as one of the potential targets for antipsychotics. A few of structurally diverse α 2C -AR antagonists have been reported, among which ORM-10921, containing one rigid tetracyclic framework with two neighboring chiral centers, has exhibited remarkable antipsychotic-like effects and pro-cognitive properties in different animal models. Yet the binding mode of ORM-10921 remains elusive. In this study, all of its four stereoisomers and a set of its analogs were synthesized and in vitro evaluated for their α 2C -AR antagonist activities. The molecular docking study and hydration site analysis gave a rational explanation for the biological results, which might provide helpful insights into the binding mode and future optimization.

show abstract

Structure‐Based Calculation of Binding Affinities of α_2A‐Adrenoceptor Agonists

et al. 2007

View full text Add to dashboard Cite

Dedicated to Professor E. Sylvester Vizi on the occasion of his 70th birthday.Adrenergic receptors of the a 2 type (a 2 -adrenoceptors) belong to the family of seven transmembrane-spanning G-proteinlinked receptors.[1-9] a 2 -Adrenoceptors can be grouped into three highly homologous subtypes (a 2A , a 2B , and a 2C ) and, because of the difference in pharmacology, [10] a fourth subtype (a 2D ) can be formally distinguished, though this is rather a species orthologue.In general, the a 2 -adrenoceptors are responsible for the presynaptic feedback of the release of adrenaline and noradrenaline, their physiological agonists. Although numerous findings are available on the receptor subtypes from experiments with knockout mice [11] and these results are of some relevance for human pharmacology, the similar patterns of expression of adrenergic receptors in human and mouse tissues do not guarantee similar functions. Thus, the individual roles of the three a 2 -adrenoceptor subtypes in humans have not been completely elucidated. However, the results of the reported studies do indicate (see Supporting Information) that the a 2 -adrenoceptor subtypes are involved in various important physiological processes, and further investigations of the differences in their molecular pharmacology are therefore essential.The identification of subtype-specific functions from pharmacological experiments is currently not possible because of the lack of subtype-specific ligands [3,[6][7][8] and the cross-reactivity with imidazoline receptors.[7] The development of subtype-selective agonists would be useful as it would facilitate further examinations of the molecular pharmacology of the a 2 -adrenoceptors. The rational, structure-based design of such agonists requires a precise knowledge of the molecular structure of the binding site. Unfortunately, because of the difficulties inherent in crystallization, atomic-resolution structures of the a 2 -adrenoceptors are not available in the Protein Databank.In the present study, an atomic-resolution model of the a 2A -adrenoceptor was constructed through use of its amino acid sequence and the crystallographic bovine rhodopsin structure as a template. Similar homology models were earlier constructed by other researchers [12] and successfully used to provide qualitative explanations. The a 2A -adrenoceptor model in the present study is based on a crystallographic template structure with a resolution of 2.2 [13] appropriate for quantitative investigations (for details, refer to the Computational Methods below).In possession of the atomic resolution target structure (a 2A -adrenoceptor), 15 known agonist ligands were automatically docked to the presumed binding region of the receptor (Figure 1 a). Inspection of the results revealed that the docked ligand conformations are in physical contact with the key residues D3.32A C H T U N G T R E N N U N G (113), S5.42A C H T U N G T R E N N U N G (200), and S5.46A C H T U N G T R E N N U N G (204), previously identified by site-directed mutagenesis studies. [1...

show abstract

Model structures of α-2 adrenoceptors in complex with automatically docked antagonist ligands raise the possibility of interactions dissimilar from agonist ligands

Cited by 27 publications

References 51 publications

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

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

Synthesis, biological evaluation, and molecular modeling of ORM‐10921 and its analogs as α_2C‐adrenoceptor antagonists

Structure‐Based Calculation of Binding Affinities of α_2A‐Adrenoceptor Agonists

Contact Info

Product

Resources

About

Model structures of α-2 adrenoceptors in complex with automatically docked antagonist ligands raise the possibility of interactions dissimilar from agonist ligands

Cited by 27 publications

References 51 publications

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

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

Synthesis, biological evaluation, and molecular modeling of ORM‐10921 and its analogs as α2C‐adrenoceptor antagonists

Structure‐Based Calculation of Binding Affinities of α2A‐Adrenoceptor Agonists

Contact Info

Product

Resources

About

Synthesis, biological evaluation, and molecular modeling of ORM‐10921 and its analogs as α_2C‐adrenoceptor antagonists

Structure‐Based Calculation of Binding Affinities of α_2A‐Adrenoceptor Agonists