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Computer-Aided Design of GPCR Ligands

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G Protein-Coupled Receptor Screening Assays

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1272))

Abstract

The recent availability of several GPCR crystal structures now contributes decisively to the perspective of structure-based ligand design. In this context, computational approaches are extremely helpful, particularly if properly integrated in drug design projects with cooperation between computational and medicinal chemistry teams. Here, we present the pipelines used in one such project, devoted to the design of novel potent and selective antagonists for the different adenosine receptors. The details of the computational strategies are described, and particular attention is given to explain how these procedures can effectively guide the synthesis of novel chemical entities.

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References

  1. Hibert M, Trumpp-Kallmeyer S, Bruinvels A, Hoflack J (1991) Three-dimensional models of neurotransmitter G-binding protein-coupled receptors. Mol Pharmacol 40:8–15

    CAS  PubMed  Google Scholar 

  2. Rasmussen SGF, Choi H-J, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VRP, Sanishvili R, Fischetti RF, Schertler GFX, Weis WI, Kobilka BK (2007) Crystal structure of the human beta2 adrenergic G-protein-coupled receptor. Nature 450:383–387

    Article  CAS  Google Scholar 

  3. Warne T, Serrano-Vega MJ, Baker JG, Moukhametzianov R, Edwards PC, Henderson R, Leslie AGW, Tate CG, Schertler GFX (2008) Structure of a beta1-adrenergic G-protein-coupled receptor. Nature 454:486–491

    Article  CAS  Google Scholar 

  4. Congreve M, Langmead CJ, Mason JS, Marshall FH (2011) Progress in structure based drug design for G protein-coupled receptors. J Med Chem 54:4283–4311

    Article  CAS  Google Scholar 

  5. Gutierrez-de-Teran H (2014) The roles of computational chemistry in the ligand design of G protein-coupled receptors: how far have we come and what should we expect? Future Med Chem 6:251–254

    Article  CAS  Google Scholar 

  6. Fredriksson R, Lagerström MC, Lundin L-G, Schiöth HB (2003) The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol 63:1256–1272

    Article  CAS  Google Scholar 

  7. Michino M, Abola E, Brooks CL, Dixon JS, Moult J, Stevens RC (2009) Community-wide assessment of GPCR structure modelling and ligand docking: GPCR Dock 2008. Nat Rev Drug Discov 8:455–463

    Article  CAS  Google Scholar 

  8. Kufareva I, Rueda M, Katritch V, Stevens RC, Abagyan R (2011) Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment. Structure 19:1108–1126

    Article  CAS  Google Scholar 

  9. Gutierrez-de-Teran H, Bello X, Rodriguez D (2013) Characterization of the dynamic events of GPCRs by automated computational simulations. Biochem Soc Trans 41:205–212

    Article  CAS  Google Scholar 

  10. Chen JF, Eltzschig HK, Fredholm BB (2013) Adenosine receptors as drug targets—what are the challenges? Nat Rev Drug Discov 12:265–286

    Article  CAS  Google Scholar 

  11. Yaziji V, Rodriguez D, Gutierrez-de-Teran H, Coelho A, Caamano O, Garcia-Mera X, Brea J, Loza MI, Cadavid MI, Sotelo E (2011) Pyrimidine derivatives as potent and selective A3 adenosine receptor antagonists. J Med Chem 54:457–471

    Article  CAS  Google Scholar 

  12. Crespo A, El Maatougui A, Biagini P, Azuaje J, Coelho A, Brea J, Loza MI, Cadavid MI, Garcia-Mera X, Gutierrez-de-Teran H, Sotelo E (2013) Discovery of 3,4-dihydropyrimidin-2(1H)-ones as a novel class of potent and selective A2B adenosine receptor antagonists. ACS Med Chem Lett 4:1031–1036

    Article  CAS  Google Scholar 

  13. Yaziji V, Rodriguez D, Coelho A, Garcia-Mera X, El Maatougui A, Brea J, Loza MI, Cadavid MI, Gutierrez-de-Teran H, Sotelo E (2013) Selective and potent adenosine A(3) receptor antagonists by methoxyaryl substitution on the N-(2,6-diarylpyrimidin-4-yl)acetamide scaffold. Eur J Med Chem 59:235–242

    Article  CAS  Google Scholar 

  14. Sali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234:779–815

    Article  CAS  Google Scholar 

  15. Sousa SF, Fernandes PA, Ramos MJ (2006) Protein-ligand docking: current status and future challenges. Proteins 65:15–26

    Article  CAS  Google Scholar 

  16. Boukharta L, Gutierrez-de-Teran H, Aqvist J (2014) Computational prediction of alanine scanning and ligand binding energetics in g-protein coupled receptors. PLoS Comput Biol 10:e1003585

    Article  Google Scholar 

  17. Goodford PJ (1985) A computational procedure for determining energetically favorable binding sites of biological important macromolecules. J Med Chem 28:849–857

    Article  CAS  Google Scholar 

  18. Pastor M, Cruciani G, McLay I, Pickett S, Clementi S (2000) GRid-INdependent descriptors (GRIND): a novel class of alignment-independent three-dimensional molecular descriptors. J Med Chem 43:3233–3243

    Article  CAS  Google Scholar 

  19. Duran A, Martinez GC, Pastor M (2008) Development and validation of AMANDA, a new algorithm for selecting highly relevant regions in molecular interaction fields. J Chem Inf Model 48:1813–1823

    Article  CAS  Google Scholar 

  20. Kristiansen K (2004) Molecular mechanisms of ligand binding, signaling, and regulation within the superfamily of G-protein-coupled receptors: molecular modeling and mutagenesis approaches to receptor structure and function. Pharmacol Ther 103:21–80

    Article  CAS  Google Scholar 

  21. Brandsdal BO, Osterberg F, Almlof M, Feierberg I, Luzhkov VB, Aqvist J (2003) Free energy calculations and ligand binding. Adv Protein Chem 66:123–158

    Article  CAS  Google Scholar 

  22. Beutler TC, Mark AE, Vanschaik RC, Gerber PR, van Gunsteren WF (1994) Avoiding singularities and numerical instabilities in free energy calculations based on molecular simulations. Chem Phys Lett 222:529–539

    Article  CAS  Google Scholar 

  23. Rodriguez D, Bello X, Gutierrez-de-Teran H (2012) Molecular modelling of G protein-coupled receptors through the Web. Mol Inform 31:334–341

    Article  CAS  Google Scholar 

  24. Jaakola V-P, Griffith MT, Hanson MA, Cherezov V, Chien EYT, Lane JR, Ijzerman AP, Stevens RC (2008) The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science 322:1211–1217

    Article  CAS  Google Scholar 

  25. Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG (1997) The CLUSTAL:X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res 25:4876–4882

    Article  CAS  Google Scholar 

  26. Davis IW, Leaver-Fay A, Chen VB, Block JN, Kapral GJ, Wang X, Murray LW, Arendall WB, Snoeyink J, Richardson JS, Richardson DC (2007) MolProbity: all-atom contacts and structure validation for proteins and nucleic acids. Nucleic Acids Res 35:W375–W383

    Article  Google Scholar 

  27. Fiser A, Do RK, Sali A (2000) Modeling of loops in protein structures. Protein Sci 9:1753–1773

    Article  CAS  Google Scholar 

  28. Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD (2003) Improved protein-ligand docking using GOLD. Proteins 52:609–623

    Article  CAS  Google Scholar 

  29. Rodrigo J, Barbany M, Gutierrez de Teran H, Centeno NB, de Caceres M, Dezi C, Fontaine F, Lozano JJ, Pastor M, Villa J, Sanz F (2002) Comparison of biomolecules on the basis of molecular interaction potentials. J Braz Chem Soc 13:795–799

    Article  CAS  Google Scholar 

  30. Dore AS, Robertson N, Errey JC, Ng I, Hollenstein K, Tehan B, Hurrell E, Bennett K, Congreve M, Magnani F, Tate CG, Weir M, Marshall FH (2011) Structure of the adenosine A2A receptor in complex with ZM241385 and the xanthines XAC and caffeine. Structure 19:1283–1293

    Article  CAS  Google Scholar 

  31. Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJC (2005) GROMACS: fast, flexible, and free. J Comput Chem 26:1701–1718

    Article  Google Scholar 

  32. JChem, version 5.10.4; ChemAxon, 2012; http://www.chemaxon.com

  33. Schrödinger Suite, version 2012; Schrödinger, LLC, 2012; http://www.schrodinger.com

  34. Pentacle, version 1.1; Molecular Discovery, Ltd., 2009; http://www.moldiscovery.com

  35. Congreve M, Andrews SP, Dore AS, Hollenstein K, Hurrell E, Langmead CJ, Mason JS, Ng IW, Tehan B, Zhukov A, Weir M, Marshall FH (2012) Discovery of 1,2,4-triazine derivatives as adenosine A(2A) antagonists using structure based drug design. J Med Chem 55:1898–1903

    Article  CAS  Google Scholar 

  36. Keranen H, Gutierrez-de-Teran H, Aqvist J (2014) Structural and energetic effects of A2A adenosine receptor mutations on agonist and antagonist binding. PLoS One 9:e108492

    Article  Google Scholar 

  37. Marelius J, Kolmodin K, Feierberg I, Åqvist J (1999) Q: an MD program for free energy calculations and empirical valence bond simulations in biomolecular systems. J Mol Graph Model 16:213–225

    Article  CAS  Google Scholar 

  38. Gutierrez-de-Teran H, Aqvist J (2012) Linear interaction energy: method and applications in drug design. Methods Mol Biol 819:305–323

    Article  Google Scholar 

  39. Rodriguez D, Pineiro A, Gutierrez-de-Teran H (2011) Molecular dynamics simulations reveal insights into key structural elements of adenosine receptors. Biochemistry 50:4194–4208

    Article  CAS  Google Scholar 

  40. Ballesteros JA, Weinstein H (1995) Integrated methods for the construction of three dimensional models and computational probing of structure-function relations in G-protein coupled receptors, In Methods Neurosci, pp 366–428, Academic Press, San Diego

    Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Cell and Molecular Biology, Biomedical Center, Uppsala University, Box 596, SE-751 24, Uppsala, Sweden

    Hugo Gutiérrez-de-Terán, Henrik Keränen & Johan Åqvist

  2. Center for Research in Biological Chemistry and Molecular Materials, University of Santiago de Compostela, A. Coruña, Spain

    Jhonny Azuaje & Eddy Sotelo

  3. Department of Biochemistry and Biophysics and Center for Biomembrane Research, Stockholm University, SE-106 91, Stockholm, Sweden

    David Rodríguez

Authors
  1. Hugo Gutiérrez-de-Terán
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  2. Henrik Keränen
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  3. Jhonny Azuaje
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  4. David Rodríguez
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  5. Johan Åqvist
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  6. Eddy Sotelo
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Corresponding author

Correspondence to Hugo Gutiérrez-de-Terán .

Editor information

Editors and Affiliations

  1. IBB – Institute for Biotechnology and Bioengineering, Lisbon, Portugal

    Duarte Miguel F. Prazeres  & Sofia Aires M. Martins  & 

  2. Department of Bioengineering, Instituto Superior Técnico Universidade de Lisboa, Lisbon, Portugal

    Duarte Miguel F. Prazeres

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Gutiérrez-de-Terán, H., Keränen, H., Azuaje, J., Rodríguez, D., Åqvist, J., Sotelo, E. (2015). Computer-Aided Design of GPCR Ligands. In: Prazeres, D.M.F., Martins, S.A.M. (eds) G Protein-Coupled Receptor Screening Assays. Methods in Molecular Biology, vol 1272. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-2336-6_19

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  • DOI: https://doi.org/10.1007/978-1-4939-2336-6_19

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-4939-2335-9

  • Online ISBN: 978-1-4939-2336-6

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