Jump to ContentJump to Main Navigation
Show Summary Details
More options …

European Pharmaceutical Journal

Acta Facultatis Pharmaceuticae Universitatis Comenianae (formerly)

2 Issues per year


CiteScore 2016: 0.28

SCImago Journal Rank (SJR) 2015: 0.195
Source Normalized Impact per Paper (SNIP) 2015: 0.202

Open Access
Online
ISSN
2453-6725
See all formats and pricing
More options …

Molecular Docking Study on the Binding Mode of Cardioselective Phenoxyaminopropanol Blocker into β-adrenergic Receptor Subtypes

M. Polakovičová
  • Corresponding author
  • Comenius University in Bratislava, Faculty of Pharmacy, Department of Chemical Theory of Drugs, Odbojarov 10, 832 32 Bratislava, Slovak Republic
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ R. Čižmáriková
  • Comenius University in Bratislava, Faculty of Pharmacy, Department of Chemical Theory of Drugs
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2012-12-28 | DOI: https://doi.org/10.2478/v10219-012-0024-6

Abstract

Structural understanding of subtype specific ligand-binding pocket variations and interactions of ligand with receptor may facilitate design of novel selective drugs. To gain insights into the subtype selectivity of β-blockers we performed flexible molecular docking study to analyze the interaction mode of cardioselective phenoxyaminopropanol blocker into the β1 and β2-adrenergic receptor. The binding site analysis reveals a strong identity between important amino acid residues and interactions with ligand in orthosteric catecholamine- binding pocket. The differences in the binding mode of selective ligand have been identified in the extracellular region of receptor subtypes.

Keywords : β-adrenergic receptor; β-blockers; selectivity; molecular docking; extracellular loops

  • Baker JG, Hill SJ, Summers RJ. Evolution of β-blockers: from anti-anginal drugs to ligand-directed signalling. Trends Pharmacol Sci. 2011;32:227-234. PubMedWeb of ScienceCrossrefGoogle Scholar

  • Ballesteros JA, Weinstein H. Integrated methods for the construction of threedimensional models and computational probing of structure-function relationship in Gprotein coupled receptors. Methods Neurosci. 1995;23:366-428 CrossrefGoogle Scholar

  • Borchard U. Pharmacological properties of β-adrenoceptor blocking drugs. J Clin Bas Cadiol. 1998;1:5-9. Google Scholar

  • Čižmarikova R, Račanska E, Hroboňova K, Lehotay J, Aghova Y, Halešova D. Synthesis and pharmacological activity and chromatographic separation of novel potential β-blockers of the aryloxyaminopropanol type. Pharmazie. 2003;58:237-241. Google Scholar

  • Heilker R, Wolff M, Tautermann ChS, Bieler M. G-protein-coupled receptor-focused drug discovery using a target class platform approach. Drug Discov Today. 2009;14:231-240. Web of SciencePubMedCrossrefGoogle Scholar

  • Hieble JP. Adrenoceptors subclassification: an approach to improved cardiovascular therapeutics. Pharmacochem Lib. 2000;31:163-171. Google Scholar

  • Horn F, Weare J, Beukers MW, et al. GPCRDB: an information system for G proteincoupled receptors. Nucleic Acids Res. 1998;26:275-279. CrossrefGoogle Scholar

  • Jaakola VP, IjzermanAP. The crystallographic structure of the adenosine A2A receptor in high-affinity antagonist-bound state: implication for GPCR drug screening and design. Curr Opinion Struct Biol. 2010;20:401-414. Web of ScienceCrossrefGoogle Scholar

  • Jacobson KA, Constanzi S. New insights for drug design from the X-ray crystallographic structure of G-protein-coupled receptors. Mol Pharmacol. 2012;82:361-371. Google Scholar

  • Johannes A, Kellershohn K, Mohr-Adra M, et al. Dualsteric GPCR targeting: a novel route to binding and signaling pathway selectivity. FASEB. 2009;23:442-450. Web of ScienceGoogle Scholar

  • Okada T, Le Trong I, Fox BA, Behnke CA, Stenkamp RE, Palczewski K. X-ray diffraction analysis of three-dimensional crystals of bovine rhodopsin obtained from mixed micelles. J Struct Biol. 2000;130:73-80. Google Scholar

  • Peeters MC, van Westen GJP, Li Q, IJzerman AP. Importance of the extracellular loops in G protein-coupled receptors for ligand recognition and activation. Trends Pharmacol Sci. 2011;32:35-42.Web of ScienceCrossrefGoogle Scholar

  • Rasmussen S, Choi H, Rosenbaum D, et al. Crystal structure of the human β2 adrenergic G-protein-coupled receptor. Nature. 2007;450:383-387. Google Scholar

  • Shoichet BK, McGovern SL, Wei B, Itwin J. Lead discovery using molecular docking. Curr Opinion Chem Biol. 2002;6:439-446. CrossrefGoogle Scholar

  • Sybyl. Molecular Modeling Software Package, Tripos mc., St. Louis MO 63144 USA, 2011. Google Scholar

  • Topiol S, Sabio M. X-ray structure breakthroughs in the GPCR transmembrane region. Biochem Pharmacol. 2009;78:11-20. CrossrefPubMedWeb of ScienceGoogle Scholar

  • Warne T, Serrano-Vega M, Baker J, et al. Structure of a β1 adrenergic G-proteincoupled receptor. Nature. 2008;454:486-491. Google Scholar

  • Warne T, Moukhametzianov R, Baker JG, et al. The structural basis for agonist and partial agonist action on a β1-adrenergic receptor. Nature. 2011;469:241-244. Web of ScienceGoogle Scholar

  • Warne T, Edwards PC, Leslie AGW, Tate C. Crystal structures of stabilized β1- adrenoceptor bound to the biased agonists bucindolol and carvedilol. Structure. 2012;20:841-849.PubMedCrossrefWeb of ScienceGoogle Scholar

About the article

Published Online: 2012-12-28


Citation Information: Acta Facultatis Pharmaceuticae Universitatis Comenianae, ISSN (Print) 0301-2298, DOI: https://doi.org/10.2478/v10219-012-0024-6.

Export Citation

This content is open access.

Comments (0)

Please log in or register to comment.
Log in