Binding site analysis of full-length α1a adrenergic receptor using homology modeling and molecular docking

Pedretti, Alessandro; Silva, Maria Elena; Villa, Luigi; Vistoli, Giulio

doi:10.1016/j.bbrc.2004.04.149

Cited by 38 publications

(23 citation statements)

References 27 publications

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“…This view is supported by the impairment of ligand binding seen for receptors mutated at D113(3.32), and by analogy to the binding mode of the catecholamines. In recent years, molecular models for receptor-ligand complexes have been constructed to support that view but in order to enforce the charge-pair interaction deviations from the bovine rhodopsin structure are often proposed (e.g., Bissantz et al, 2003;Ishiguro et al, 2002;Pedretti et al, 2004). In the present study, manual docking of antagonists was required to enforce the charge-pair interaction: the ligands are shifted away from TM5 and towards TM2 and TM7, atoms of the ligands overlap with the receptor, and the antagonists do not fully occupy the binding cavity.…”

Section: Discussionmentioning

confidence: 99%

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

Xhaard

Nyrönen

Rantanen

et al. 2005

Journal of Structural Biology

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Section: Discussionmentioning

confidence: 99%

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

Xhaard

Nyrönen

Rantanen

et al. 2005

Journal of Structural Biology

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“…The second extracellular loop (EC-II), moves further into the TM framework allowing for the participation of EC-II residues (Thr-174, Cys-176, Gln-177 and Ile-178) in the binding site as observed by Pedretti et al [26].…”

Section: Resultsmentioning

confidence: 91%

Modelling the Interaction of Catecholamines with the α1A Adrenoceptor Towards a Ligand-induced Receptor Structure

Kinsella¹,

Rozas²,

Watson³

2005

J Comput Aided Mol Des

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Adrenoceptors are members of the important G protein coupled receptor family for which the detailed mechanism of activation remains unclear. In this study, we have combined docking and molecular dynamics simulations to model the ligand induced effect on an homology derived human alpha1A adrenoceptor. Analysis of agonist/alpha1A adrenoceptor complex interactions focused on the role of the charged amine group, the aromatic ring, the N-methyl group of adrenaline, the beta hydroxyl group and the catechol meta and para hydroxyl groups of the catecholamines. The most critical interactions for the binding of the agonists are consistent with many earlier reports and our study suggests new residues possibly involved in the agonist-binding site, namely Thr-174 and Cys-176. We further observe a number of structural changes that occur upon agonist binding including a movement of TM-V away from TM-III and a change in the interactions of Asp-123 of the conserved DRY motif. This may cause Arg-124 to move out of the TM helical bundle and change the orientation of residues in IC-II and IC-III, allowing for increased affinity of coupling to the G-protein.

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“…α 1D -AR is a member of the G protein—coupled receptors (GPCRs) family that are constructed by seven transmembrane (TM) helices, N- and C-terminal fragments, and intra- and extracellular loop (ECL) regions21, 22. Molecular docking was performed on α 1D receptor constructed by homology model building using the AutoDock-vina program since the accurate 3D structures of α 1D -AR with high resolutions has not been obtained yet 12 .…”

Section: Resultsmentioning

confidence: 99%

Crystal structures, absolute configurations and molecular docking studies of naftopidil enantiomers as α 1D -adrenoceptor antagonists

Xü

Huang

Jiang

et al. 2017

Acta Pharmaceutica Sinica B

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Chiral drug naftopidil (NAF), a specific α1D-adrenoceptor (AR) antagonist for the treatment of benign prostatic hyperplasia, was used in racemic form for several decades. Our recent work declared that NAF enantiomers showed the same antagonistic effects on the α1D-AR, but the binding mechanism of these two stereochemical NAF isomers to the α1D receptor remained unclear. Herein, we reported the crystallographic structures of optically pure NAF stereoisomers for the first time and unambiguously determined their absolute configurations. The crystal data of R and S enantiomers matched satisfactorily the pharmacophore model for α1D-selective antagonists. Based on the constructed α1D homology model, molecular docking studies shed light on the molecular mechanism of NAF enantiomers binding to α1D-AR. The results indicated that NAF enantiomers exhibited the very similar binding poses and occupied the same binding pocket.

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Binding site analysis of full-length α1a adrenergic receptor using homology modeling and molecular docking

Cited by 38 publications

References 27 publications

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

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

Modelling the Interaction of Catecholamines with the α1A Adrenoceptor Towards a Ligand-induced Receptor Structure

Crystal structures, absolute configurations and molecular docking studies of naftopidil enantiomers as α 1D -adrenoceptor antagonists

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