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

M. Polakovičová 1  and R. Čižmáriková 2
  • 1 Comenius University in Bratislava, Faculty of Pharmacy, Department of Chemical Theory of Drugs, Odbojarov 10, 832 32 Bratislava, Slovak Republic
  • 2 Comenius University in Bratislava, Faculty of Pharmacy, Department of Chemical Theory of Drugs


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.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 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.

  • 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

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

  • 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.

  • 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.

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

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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

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

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

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

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

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

  • 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.

  • 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.


Journal + Issues