Journal of Molecular Modeling

, Volume 16, Issue 3, pp 401–409 | Cite as

Docking studies on a refined human β2 adrenoceptor model yield theoretical affinity values in function with experimental values for R-ligands, but not for S-antagonists

  • Marvin A. Soriano-Ursúa
  • José G. Trujillo-Ferrara
  • Jesús Álvarez-Cedillo
  • José Correa-Basurto
Original Paper
First Online:
Received:
Accepted:

Abstract

G-protein coupled receptors (GPCR) belong to the largest group of membrane proteins involved in signal transduction. These receptors are implicated in diverse physiological and pathological events. The human β2 adrenergic receptor (hβ2AR) is one of the few GPCRs whose 3-D structures are available on the Protein Data Bank. Because there is great interest by drug developers for hβ2AR as a target, it is necessary to study its ligand-recognition process at the atomic level. The hβ2AR can recognize both R/S enantiomeric ligands, R-agonists result in a greater activation than do S-agonists (eutomers and distomers for activation, respectively), according to experimental results. In this work is reported the ligand recognition on a refined hβ2AR-structure of a set of well-known R/S-ligands by means of docking studies. Data obtained in silico were analyzed and compared with those reported in vitro. The theoretical affinity values were reproduced for agonists, but not for antagonist (or inverse agonists). However, theoretical data for R-antagonists are in function to experimental data. The theoretical results confirm the role of amino acids previously reported by mutagenesis studies due to their important roles in drug affinity and stereoselectivity.

Keywords

β2 adrenergic receptor Docking Eutomer Stereoselectivity 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

This work was supported by grants from Consejo Nacional de Ciencia Y Tecnología (CONACyT) (62488) and Comisión de Operación y Fomento de Actividades Académicas -Sección de Investigación y Posgrado del Instituto Politécnico Nacional (20080026). We would also like to thank Ian Ilizaliturri Flores for building and supporting the cluster used to run docking simulations.

References

  1. 1.
    Kolb P, Rosenbaum DM, Irwin JJ, Fung JJ, Kobilka BK, Shoichet BK (2009) Structure-based discovery of beta2-adrenergic receptor ligands. Proc Natl Acad Sci USA 106:6843–6848CrossRefGoogle Scholar
  2. 2.
    Yu IW, Bukaveckas BL (2008) Pharmacogenetic tests in asthma therapy. Clin Lab Med 28:645–665CrossRefGoogle Scholar
  3. 3.
    Rubenstein LA, Zauhar RJ, Lanzara RG (2006) Molecular dynamics of a biophysical model for beta2-adrenergic and G protein-coupled receptor activation. J Mol Graph Model 25:396–409CrossRefGoogle Scholar
  4. 4.
    Savarese TM, Fraser CM (1992) In vitro mutagenesis and the search for structure-function relationships among G protein-coupled receptors. Biochem J 283:1–19Google Scholar
  5. 5.
    Chelikani P, Hornak V, Eilers M, Reeves PJ, Smith SO, RajBhandary UL, Khorana HG (2007) Role of group-conserved residues in the helical core of beta2-adrenergic receptor. Proc Natl Acad Sci USA 104:7027–7032CrossRefGoogle Scholar
  6. 6.
    Bhattacharya S, Hall SE, Li H, Vaidehi N (2008) Ligand stabilized conformational states of human beta 2 adrenergic receptor: insight into G protein coupled receptor activation. Biophys J 94:2027–2042CrossRefGoogle Scholar
  7. 7.
    Huber T, Menon S, Sakmar TP (2008) Structural basis for ligand binding and specificity in adrenergic receptors: implications for GPCR-targeted drug discovery. Biochem 47:11013–11023CrossRefGoogle Scholar
  8. 8.
    Audet M, Bouvier M (2008) Insights into signaling from the β2-adrenergic receptor structure. Nat Chem Biol 4:397–403CrossRefGoogle Scholar
  9. 9.
    Costanzi S (2008) On the applicability of GPCR models to Computer-aided Drug Discovery: a comparison between in silico and crystal structure of the β2-adrenergic receptor. J Med Chem 51:2907–2914CrossRefGoogle Scholar
  10. 10.
    Spijker P, Vaidehi N, Freddolino LP, Hilbers PAJ, Goddard WA (2006) Dynamic behavior of fully solvated β2-adrenergic receptor, embedded in the membrane with bound agonist or antagonist. Proc Natl Acad Sci USA 103:4882–4887CrossRefGoogle Scholar
  11. 11.
    Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK (2007) GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function. Science 318:1266–1273CrossRefGoogle Scholar
  12. 12.
    Swaminath G, Xiang Y, Lee TW, Steenhuis J, Parnot C, Kobilka BK (2004) Sequential binding of agonists to the β2 adrenoceptor. J Biol Chem 279:686–691CrossRefGoogle Scholar
  13. 13.
    Ambrosio C, Molinari P, Cotecchia S, Costa T (2000) Catechol-binding serines of beta(2)-adrenergic receptors control the equilibrium between active and inactive receptor states. Mol Pharmacol 57:198–210Google Scholar
  14. 14.
    Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC (2007) High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science 318:1258–1265CrossRefGoogle Scholar
  15. 15.
    Phillips JC, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E, Chipot C, Skeel RD, Kale L, Schulten K (2005) Scalable molecular dynamics with NAMD. J Comp Chem 26:1781–1802CrossRefGoogle Scholar
  16. 16.
    Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:33–38CrossRefGoogle Scholar
  17. 17.
    Laurie AT, Jackson RM (2005) Q-SiteFinder: an energy-based method for the prediction of protein-ligand binding sites. Bioinf 21:1908–1916CrossRefGoogle Scholar
  18. 18.
    Soriano-Ursúa MA, Valencia-Hernández I, Arellano-Mendoza MG, Correa-Basurto J, Trujillo-Ferrara JG (2009) Synthesis, pharmacological and in silico evaluation of 1-(4-di-hydroxy-3, 5-dioxa-4-borabicyclo[4.4.0]deca-7, 9, 11-trien-9-yl)-2-(tert-butyl-amino)ethanol, a compound designed to act as a β2 adrenoceptor agonist. Eur J Med Chem 44:2840–2846CrossRefGoogle Scholar
  19. 19.
    Frisch MJ, Trucks GW, Schlegel HB et al (1998) Gaussian 98, Version A.7. Gaussian Inc, PittsburghGoogle Scholar
  20. 20.
    Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a Lamarckian genetic algorithm and empirical binding free energy function. J Comp Chem 19:1639–1662CrossRefGoogle Scholar
  21. 21.
    Goodford PJ (1985) A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. J Med Chem 28:849–857CrossRefGoogle Scholar
  22. 22.
    Swaminath G, Deupi X, Lee TW, Zhu W, Thian FS, Kobilka TS, Kobilka B (2005) Probing the β2 adrenoceptor binding site with catechol reveals differences in binding and activation by agonist and partial agonists. J Biol Chem 280:22165–22171CrossRefGoogle Scholar
  23. 23.
    Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK (2007) Crystal structure of the human beta2 adrenergic G-protein-coupled receptor. Nature 450:383–387CrossRefGoogle Scholar
  24. 24.
    January B, Siebold A, Whaley B, Hiplin RW, Lin D, Schonbrunn A, Barber R, Clark RB (1997) beta(2)-adrenergic receptor desensitization, internalization and phosphorylation in response to full and partial agonists. J Biol Chem 272:23871–23879CrossRefGoogle Scholar
  25. 25.
    Liapakis G, Chan WC, Papadokostaki M, Javitch JA (2004) Synergistic contributions of the functional groups of epinephrine to its affnity and efficacy at the beta(2)-adrenergic receptor. Mol Pharmacol 65:1181–1190CrossRefGoogle Scholar
  26. 26.
    Baker JG (2005) The selectivity of beta-adrenoceptor antagonists at the human beta1, beta2 and beta3 adrenoceptors. Br J Pharmacol 144:317–322CrossRefGoogle Scholar
  27. 27.
    Wieland K, Zuurmond HM, Krasel C, Ijzerman AP, Lohse MJ (1996) Involvement of Asn-293 in stereospecif agonist recognition and in activation of the beta 2-adrenergic receptor. Proc Natl Acad Sci USA 93:9276–9281CrossRefGoogle Scholar
  28. 28.
    Hannawacker A, Krasel C, Lohse MJ (2002) Mutation of Asn293 to Asp in transmembrane helix VI abolishes agonist-induced but not constitutive activity of the beta(2)-adrenergic receptor. Mol Pharmacol 62:1431–1437CrossRefGoogle Scholar
  29. 29.
    Kikkawa H, Isogaya M, Nagao T, Kurose H (1998) The role of the seventh transmembrane region in high affinity binding of a beta 2-selective agonist TA-2005. Mol Pharmacol 53:128–134Google Scholar
  30. 30.
    O’Dowd BF, Hnatowich M, Regan JW, Leader WM, Caron MG, Lefkowitz RJ (1988) Site-directed mutagenesis of the cytoplasmic domains of the human beta 2-adrenergic receptor. Localization of regions involved in G protein-receptor coupling. J Biol Chem 263:15985–15992Google Scholar
  31. 31.
    De Graaf C, Rognan D (2008) Selective structure-based virtual screening for full and partial agonist of the β2 adrenergic receptor. J Med Chem 51:4978–4985CrossRefGoogle Scholar
  32. 32.
    Brooks WH, Daniel KG, Sung SS, Guida WC (2008) Computational validation of the importance of absolute stereochemistry in virtual screening. J Chem Inf Model 48:639–645CrossRefGoogle Scholar
  33. 33.
    Kobilka BK (2007) G protein coupled receptor structure and activation. Biochim Biophys Acta 1768:794–807CrossRefGoogle Scholar
  34. 34.
    Fraser CM (1989) Site-directed mutagenesis of beta adrenergic receptors. Identification of conserved cysteine residues that independently affect ligand binding and receptor activation. J Biol Chem 264:9266–9270Google Scholar
  35. 35.
    Fatakia SN, Costanzi S, Chow CC (2009) Computing highly correlated positions using mutual information and graph theory for G protein-coupled receptors. PLoS One 4:e4681CrossRefGoogle Scholar
  36. 36.
    Warne T, Serrano-Vega MJ, Baker JG, Moukhametzianov R, Edwards PC, Henderson R, Leslie AG, Tate CG, Schertler GF (2008) Structure of a β1 adrenergic G-protein coupled receptor. Nature 454:486–492CrossRefGoogle Scholar
  37. 37.
    Mustafi D, Palczewski K (2009) Topology of class A G protein-coupled receptors: insights gained from crystal structures of rhodopsins, adrenergic and adenosine receptors. Mol Pharmacol 75:1–12CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Marvin A. Soriano-Ursúa
    • 1
    • 2
  • José G. Trujillo-Ferrara
    • 2
  • Jesús Álvarez-Cedillo
    • 3
  • José Correa-Basurto
    • 4
  1. 1.Departamento de Fisiología y Farmacología, Escuela Superior de MedicinaInstituto Politécnico NacionalMéxicoMexico
  2. 2.Departamento de Bioquímica, Escuela Superior de MedicinaInstituto Politécnico NacionalMéxicoMexico
  3. 3.Laboratorio de Procesamiento Paralelo de la Sección de Estudios de Posgrado e InvestigaciónCentro de Innovación y Desarrollo Tecnológico en Cómputo (CIDETEC-IPN)MéxicoMexico
  4. 4.Laboratorio de Modelado Molecular de la Sección de Estudios de Posgrado e Investigación, Escuela Superior de MedicinaInstituto Politécnico NacionalMéxicoMexico

Personalised recommendations