Molecular Modelling Approaches for the Analysis of Histamine Receptors and Their Interaction with Ligands

Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 241)

Abstract

Several experimental techniques to analyse histamine receptors are available, e.g. pharmacological characterisation of known or new compounds by different types of assays or mutagenesis studies. To obtain insights into the histamine receptors on a molecular and structural level, crystal structures have to be determined and molecular modelling studies have to be performed. It is widely accepted to generate homology models of the receptor of interest based on an appropriate crystal structure as a template and to refine the resulting models by molecular dynamic simulations. A lot of modelling techniques, e.g. docking, QSAR or interaction fingerprint methods, are used to predict binding modes of ligands and pharmacological data, e.g. affinity or even efficacy. However, within the last years, molecular dynamic simulations got more and more important: First of all, molecular dynamic simulations are very helpful to refine the binding mode of a ligand to a histamine receptor, obtained by docking studies. Furthermore, with increasing computational performance it got possible to simulate complete binding pathways of ions or ligands from the aqueous extracellular phase into the allosteric or orthosteric binding pocket of histamine receptors.

Keywords

Histamine receptors Homology modelling Molecular dynamics Molecular modelling 

Abbreviations

E2-loop

Extracellular loop E2

GPCR

G protein-coupled receptor

gpH1R

Guinea-pig histamine H1 receptor

h5-HT1BR

Human serotonine 5-HT1B receptor

h5-HT2BR

Human serotonine 5-HT2B receptor

hD3R

Human dopamine D3 receptor

hH1R

Human histamine H1 receptor

hH2R

Human histamine H2 receptor

hH3R

Human histamine H3 receptor

hH4R

Human histamine H4 receptor

hM2R

Human muscarinic M2 receptor

2R

Human adrenergic β2 receptor

MD

Molecular dynamics

MM

Molecular mechanics

QM

Quantum mechanics

QSAR

Quantitative structure activity relationship

1R

Turkey adrenergic β1 receptor

xHxR

Different species of the four histamine receptor subtypes

References

  1. Arora B, Coudrat T, Wootten D, Christopoulos A, Noronha SB, Sexton PM (2016) Prediction of loops in G protein-coupled receptor homology models: effect of imprecise surroundings and constraints. J Chem Inf Model 56:671–686PubMedCrossRefGoogle Scholar
  2. Bakker RA, Weiner DM, ter Laak T, Beuming T, Zuiderveld OP, Edelbroek M, Hacksell U, Timmerman H, Brann MR, Leurs R (2004) 8R-lisuride is a potent stereospecific histamine H1-receptor partial agonist. Mol Pharmacol 65:538–549PubMedCrossRefGoogle Scholar
  3. Beuming T, Sherman W (2012) Current assessment of docking into GPCR crystal structures and homology models: successes, challenges, and guidelines. J Chem Inf Model 52:3263–3277PubMedCrossRefGoogle Scholar
  4. Beuming T, Lenselink B, Pala D, McRobb F, Repasky M, Sherman W (2015) Docking and virtual screening strategies for GPCR drug discovery. Methods Mol Biol 1335:251–276PubMedCrossRefGoogle Scholar
  5. Bokoch MP, Zou Y, Rasmussen SG, Liu CW, Nygaard R, Rosenbaum DM, Fung JJ, Choi HJ, Thian FS, Kobilka TS, Puglisi JD, Weis WI, Pardo L, Prosser RS, Mueller L, Kobilka BK (2010) Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor. Nature 463:108–112PubMedPubMedCentralCrossRefGoogle Scholar
  6. Brunskole I, Strasser A, Seifert R, Buschauer A (2011) Role of the second and third extracellular loops of the histamine H(4) receptor in receptor activation. Naunyn Schmiedebergs Arch Pharmacol 384:301–317PubMedCrossRefGoogle Scholar
  7. Bruysters M, Pertz HH, Teunissen A, Bakker RA, Gillard M, Chatelain P, Schunack W, Timmerman H, Leurs R (2004) Mutational analysis of the histamine H1-receptor binding pocket of histaprodifens. Eur J Pharmacol 487:55–63PubMedCrossRefGoogle Scholar
  8. Bruysters M, Jongejan A, Gillard M, van de Manakker F, Bakker RA, Chatelain P, Leurs R (2005) Pharmacological differences between human and guinea pig histamine H1 receptors: Asn84 (2.61) as key residue within an additional binding pocket in the H1 receptor. Mol Pharmacol 67:1045–1052PubMedCrossRefGoogle Scholar
  9. Chaudhari R, Heim AJ, Li Z (2015) Improving homology modeling of G-protein coupled receptors through multiple-template derived conserved inter-residue interactions. J Comput Aided Mol Des 29:413–420PubMedCrossRefGoogle Scholar
  10. 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 318:1258–1265PubMedPubMedCentralCrossRefGoogle Scholar
  11. Cherkasov A, Muratov EN, Fourches D, Varnek A, Baskin II, Cronin M, Dearden J, Gramatica P, Martin YC, Todeschini R, Consonni V, Kuz’min VE, Cramer R, Benigni R, Yang C, Rathman J, Terfloth L, Gasteiger J, Richard A, Tropsha A (2014) QSAR modeling: where have you been? Where are you going to? J Med Chem 57:4977–5010PubMedPubMedCentralCrossRefGoogle Scholar
  12. Chien EY, Liu W, Zhao Q, Katritch V, Han GW, Hanson MA, Shi L, Newman AH, Javitch JA, Cherezov V, Stevens RC (2010) Structure of the human dopamine D3 receptor in complex with D2/D3 selective antagonist. Science 330:1091–1095PubMedPubMedCentralCrossRefGoogle Scholar
  13. Christopher JA, Brown J, Dore AS, Errey JC, Koglin M, Marshall FH, Myszka DG, Rich RL, Tate CG, Tehan B, Warne T, Congreve M (2013) Biophysical fragment screening of the beta1-adrenergic receptor: identification of high affinity arylpiperazine leads using structure-based drug design. J Med Chem 56:3446–3455PubMedPubMedCentralCrossRefGoogle Scholar
  14. Ciancetta A, Sabbadin D, Federico S, Spalluto G, Moro S (2015) Advances in computational techniques to study GPCR-ligand recognition. Trends Pharmacol Sci 36:878–890PubMedCrossRefGoogle Scholar
  15. Costanzi S (2012) Homology modeling of class a G protein-coupled receptors. Methods Mol Biol 857:259–279PubMedPubMedCentralCrossRefGoogle Scholar
  16. Costanzi S (2013) Modeling G protein-coupled receptors and their interactions with ligands. Curr Opin Struct Biol 23:185–190PubMedCrossRefGoogle Scholar
  17. Damale MG, Harke SN, Kalam Khan FA, Shinde DB, Sangshetti JN (2014) Recent advances in multidimensional QSAR (4D-6D): a critical review. Mini Rev Med Chem 14:35–55PubMedCrossRefGoogle Scholar
  18. Darras FH, Pockes S, Huang G, Wehle S, Strasser A, Wittmann HJ, Nimczick M, Sotriffer CA, Decker M (2014) Synthesis, biological evaluation, and computational studies of Tri- and tetracyclic nitrogen-bridgehead compounds as potent dual-acting AChE inhibitors and hH3 receptor antagonists. ACS Chem Nerosci 5:225–242CrossRefGoogle Scholar
  19. de Graaf C, Rognan D (2009) Customizing G Protein-coupled receptor models for structure-based virtual screening. Curr Pharm Des 15:4026–4048PubMedCrossRefGoogle Scholar
  20. Deng Z, Chuaqui C, Singh J (2004) Structural interaction fingerprint (SIFt): a novel method for analyzing three-dimensional protein-ligand binding interactions. J Med Chem 47:337–344PubMedCrossRefGoogle Scholar
  21. Dror RO, Pan AC, Arlow DH, Borhani DW, Maragakis P, Shan Y, Xu H, Shaw DE (2011) Pathway and mechanism of drug binding to G-protein-coupled receptors. Proc Natl Acad Sci U S A 108:13118–13123PubMedPubMedCentralCrossRefGoogle Scholar
  22. Dror RO, Dirks RM, Grossman JP, Xu H, Shaw DE (2012) Biomolecular simulation: a computational microscope for molecular biology. Annu Rev Biophys 41:429–452PubMedCrossRefGoogle Scholar
  23. Elz S, Kramer K, Pertz HH, Detert H, ter Laak AM, Kuhne R, Schunack W (2000) Histaprodifens: synthesis, pharmacological in vitro evaluation, and molecular modeling of a new class of highly active and selective histamine H(1)-receptor agonists. J Med Chem 43:1071–1084PubMedCrossRefGoogle Scholar
  24. Filizola ME (2014) G protein-coupled receptors—modeling and simulation. Springer, Dordrecht. ISBN 978-94-007-7423-0Google Scholar
  25. Filizola M, Carteni-Farina M, Perez JJ (1999) Modeling the 3D structure of rhodopsin using a de novo approach to build G-protein-coupled receptors. J Phys Chem B 103:2520–2527CrossRefGoogle Scholar
  26. Fiser A (2010) Template-based protein structure modeling. Methods Mol Biol 673:73–94PubMedPubMedCentralCrossRefGoogle Scholar
  27. Geyer R, Nordemann U, Strasser A, Wittmann HJ, Buschauer A (2016) Conformational restriction and enantioseparation increase potency and selectivity of cyanoguanidine-type histamine H4 receptor agonists. J Med Chem 59:3452–3470PubMedCrossRefGoogle Scholar
  28. Goldfeld DA, Zhu K, Beuming T, Friesner RA (2011) Successful prediction of the intra- and extracellular loops of four G-protein-coupled receptors. Proc Natl Acad Sci U S A 108:8275–8280PubMedPubMedCentralCrossRefGoogle Scholar
  29. Haga K, Kruse AC, Asada H, Yurugi-Kobayashi T, Shiroishi M, Zhang C, Weis WI, Okada T, Kobilka BK, Haga T, Kobayashi T (2012) Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist. Nature 482:547–551PubMedPubMedCentralCrossRefGoogle Scholar
  30. Hanson MA, Cherezov V, Griffith MT, Roth CB, Jaakola VP, Chien EY, Velasquez J, Kuhn P, Stevens RC (2008) A specific cholesterol binding site is established by the 2.8 Å structure of the human beta2-adrenergic receptor. Structure 16:897–905PubMedPubMedCentralCrossRefGoogle Scholar
  31. Heifetz A, Chudyk EI, Gleave L, Aldeghi M, Cherezov V, Fedorov DG, Biggin PC, Bodkin MJ (2016a) The fragment molecular orbital method reveals new insight into the chemical nature of GPCR-ligand interactions. J Chem Inf Model 56:159–172PubMedCrossRefGoogle Scholar
  32. Heifetz A, James T, Morao I, Bodkin MJ, Biggin PC (2016b) Guiding lead optimization with GPCR structure modeling and molecular dynamics. Curr Opin Pharmacol 30:14–21PubMedCrossRefGoogle Scholar
  33. Henderson R, Baldwin JM, Ceska TA, Zemlin F, Beckmann E, Downing KH (1990) Model for the structure of bacteriorhodopsin based on high-resolution electron cryo-microscopy. J Mol Biol 213:899–929PubMedCrossRefGoogle Scholar
  34. Huang J, Chen S, Zhang JJ, Huang XY (2013) Crystal structure of oligomeric beta1-adrenergic G protein-coupled receptors in ligand-free basal state. Nat Struct Mol Biol 20:419–425PubMedPubMedCentralCrossRefGoogle Scholar
  35. Huang CY, Olieric V, Ma P, Howe N, Vogeley L, Liu X, Warshamanage R, Weinert T, Panepucci E, Kobilka B, Diederichs K, Wang M, Caffrey M (2016) In meso in situ serial X-ray crystallography of soluble and membrane proteins at cryogenic temperatures. Acta Crystallogr D Struct Biol 72:93–112PubMedPubMedCentralCrossRefGoogle Scholar
  36. Irwin JJ, Shoichet BK (2016) Docking screens for novel ligands conferring new biology. J Med Chem 59:4103–4120PubMedPubMedCentralCrossRefGoogle Scholar
  37. Istyastono EP, Nijmeijer S, Lim HD, van de Stolpe A, Roumen L, Kooistra AJ, Vischer HF, de Esch IJ, Leurs R, de Graaf C (2011) Molecular determinants of ligand binding modes in the histamine H(4) receptor: linking ligand-based three-dimensional quantitative structure-activity relationship (3D-QSAR) models to in silico guided receptor mutagenesis studies. J Med Chem 54:8136–8147PubMedCrossRefGoogle Scholar
  38. Jongejan A, Bruysters M, Ballesteros JA, Haaksma E, Bakker RA, Pardo L, Leurs R (2005) Linking agonist binding to histamine H1 receptor activation. Nat Chem Biol 1:98–103PubMedCrossRefGoogle Scholar
  39. Jongejan A, Lim HD, Smits RA, de Esch IJ, Haaksma E, Leurs R (2008) Delineation of agonist binding to the human histamine H4 receptor using mutational analysis, homology modeling, and ab initio calculations. J Chem Inf Model 48:1455–1463PubMedCrossRefGoogle Scholar
  40. Katritch V, Fenalti G, Abola EE, Roth BL, Cherezov V, Stevens RC (2014) Allosteric sodium in class A GPCR signaling. Trends Biochem Sci 39:233–244PubMedPubMedCentralCrossRefGoogle Scholar
  41. Kiss R, Noszal B, Racz A, Falus A, Eros D, Keseru GM (2008) Binding mode analysis and enrichment studies on homology models of the human histamine H4 receptor. Eur J Med Chem 43:1059–1070PubMedCrossRefGoogle Scholar
  42. Koehler Leman J, Ulmschneider MB, Gray JJ (2015) Computational modeling of membrane proteins. Proteins 83:1–24PubMedCrossRefGoogle Scholar
  43. Kooistra AJ, Kuhne S, De Esch IJ, Leurs R, De Graaf C (2013) A structural chemogenomics analysis of aminergic GPCRs: lessons for histamine receptor ligand design. Br J Pharmacol 170:101–126PubMedPubMedCentralCrossRefGoogle Scholar
  44. Kooistra AJ, de Graaf C, Timmerman H (2014) The receptor concept in 3D: from hypothesis and metaphor to GPCR-ligand structures. Neurochem Res 39:1850–1861PubMedCrossRefGoogle Scholar
  45. Kooistra AJ, Vischer HF, McNaught-Flores D, Leurs R, de Esch IJ, de Graaf C (2016) Function-specific virtual screening for GPCR ligands using a combined scoring method. Sci Rep 6:28288PubMedPubMedCentralCrossRefGoogle Scholar
  46. Kovalainen JT, Christiaans JAM, Ropponen R, Poso A, Perakyla M, Vepsalainen J, Laatikainen R, Gynther J (2000) A proton relay process as the mechanism of activation of the histamine H3-receptor determined by 1H NMR and ab initio quantum mechanical calculations. J Am Chem Soc 122:6989–6996CrossRefGoogle Scholar
  47. Kuhne S, Kooistra AJ, Bosma R, Bortolato A, Wijtmans M, Vischer HF, Mason JS, de Graaf C, de Esch IJ, Leurs R (2016) Identification of ligand binding hot spots of the histamine H1 receptor following structure-based fragment optimization. J Med Chem 59:9047–9061PubMedCrossRefGoogle Scholar
  48. Kumari P, Ghosh E, Shukla AK (2015) Emerging approaches to GPCR ligand screening for drug discovery. Trends Mol Med 21:687–701PubMedCrossRefGoogle Scholar
  49. Leschke C, Elz S, Garbarg M, Schunack W (1995) Synthesis and histamine H1 receptor agonist activity of a series of 2-phenylhistamines, 2-heteroarylhistamines, and analogues. J Med Chem 38:1287–1294PubMedCrossRefGoogle Scholar
  50. Leslie AG, Warne T, Tate CG (2015) Ligand occupancy in crystal structure of beta1-adrenergic G protein-coupled receptor. Nat Struct Mol Biol 22:941–942PubMedPubMedCentralCrossRefGoogle Scholar
  51. Levoin N, Labeeuw O, Billot X, Calmels T, Danvy D, Krief S, Berrebi-Bertrand I, Lecomte JM, Schwartz JC, Capet M (2016) Discovery of nanomolar ligands with novel scaffolds for the histamine H4 receptor by virtual screening. Eur J Med Chem 125:565–572PubMedCrossRefGoogle Scholar
  52. Lim HD, Jongejan A, Bakker RA, Haaksma E, de Esch IJ, Leurs R (2008) Phenylalanine 169 in the second extracellular loop of the human histamine H4 receptor is responsible for the difference in agonist binding between human and mouse H4 receptors. J Pharmacol Exp Ther 327:88–96PubMedCrossRefGoogle Scholar
  53. Malinowska B, Piszcz J, Schlicker E, Kramer K, Elz S, Schunack W (1999) Histaprodifen, methylhistaprodifen, and dimethylhistaprodifen are potent H1-receptor agonists in the pithed and in the anaesthetized rat. Naunyn Schmiedebergs Arch Pharmacol 359:11–16PubMedCrossRefGoogle Scholar
  54. McRobb FM, Negri A, Beuming T, Sherman W (2016) Molecular dynamics techniques for modeling G protein-coupled receptors. Curr Opin Pharmacol 30:69–75PubMedCrossRefGoogle Scholar
  55. Menghin S, Pertz HH, Kramer K, Seifert R, Schunack W, Elz S (2003) N(alpha)-imidazolylalkyl and pyridylalkyl derivatives of histaprodifen: synthesis and in vitro evaluation of highly potent histamine H(1)-receptor agonists. J Med Chem 46:5458–5470PubMedCrossRefGoogle Scholar
  56. Miller-Gallacher JL, Nehme R, Warne T, Edwards PC, Schertler GF, Leslie AG, Tate CG (2014) The 2.1 A resolution structure of cyanopindolol-bound beta1-adrenoceptor identifies an intramembrane Na+ ion that stabilises the ligand-free receptor. PLoS One 9:e92727PubMedPubMedCentralCrossRefGoogle Scholar
  57. Mobarec JC, Sanchez R, Filizola M (2009) Modern homology modeling of G-protein coupled receptors: which structural template to use? J Med Chem 52:5207–5216PubMedPubMedCentralCrossRefGoogle Scholar
  58. Mordalski S, Kosciolek T, Kristiansen K, Sylte I, Bojarski AJ (2011) Protein binding site analysis by means of structural interaction fingerprint patterns. Bioorg Med Chem Lett 21:6816–6819PubMedCrossRefGoogle Scholar
  59. Moukhametzianov R, Warne T, Edwards PC, Serrano-Vega MJ, Leslie AG, Tate CG, Schertler GF (2011) Two distinct conformations of helix 6 observed in antagonist-bound structures of a beta1-adrenergic receptor. Proc Natl Acad Sci U S A 108:8228–8232PubMedPubMedCentralCrossRefGoogle Scholar
  60. Munk C, Harpsoe K, Hauser AS, Isberg V, Gloriam DE (2016) Integrating structural and mutagenesis data to elucidate GPCR ligand binding. Curr Opin Pharmacol 30:51–58PubMedCrossRefGoogle Scholar
  61. Naporra F, Gobleder S, Wittmann HJ, Spindler J, Bodensteiner M, Bernhardt G, Hubner H, Gmeiner P, Elz S, Strasser A (2016) Dibenzo[b,f][1,4]oxazepines and dibenzo[b,e]oxepines: Influence of the chlorine substitution pattern on the pharmacology at the H1R, H4R, 5-HT2AR and other selected GPCRs. Pharmacol Res 113:610–625PubMedCrossRefGoogle Scholar
  62. Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M (2000) Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289:739–745PubMedCrossRefGoogle Scholar
  63. Panula P, Chazot PL, Cowart M, Gutzmer R, Leurs R, Liu WL, Stark H, Thurmond RL, Haas HL (2015) International union of basic and clinical pharmacology. XCVIII. Histamine receptors. Pharmacol Rev 67:601–655PubMedPubMedCentralCrossRefGoogle Scholar
  64. Peeters MC, van Westen GJ, Li Q, IJzerman AP (2011) Importance of the extracellular loops in G protein-coupled receptors for ligand recognition and receptor activation. Trends Pharmacol Sci 32:35–42PubMedCrossRefGoogle Scholar
  65. Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VRP, Sansihvili R, Fischetti RF, Schertler GFX, Weis WI, Kobilka BK (2007) Crystal structure of the human beta 2 adrenergic G protein-coupled receptor. Nature 450:383–387PubMedCrossRefGoogle Scholar
  66. Rasmussen SG, Choi HJ, Fung JJ, Pardon E, Casarosa P, Chae PS, Devree BT, Rosenbaum DM, Thian FS, Kobilka TS, Schnapp A, Konetzki I, Sunahara RK, Gellman SH, Pautsch A, Steyaert J, Weis WI, Kobilka BK (2011a) Structure of a nanobody-stabilized active state of the beta(2) adrenoceptor. Nature 469:175–180PubMedPubMedCentralCrossRefGoogle Scholar
  67. Rasmussen SG, DeVree BT, Zou Y, Kruse AC, Chung KY, Kobilka TS, Thian FS, Chae PS, Pardon E, Calinski D, Mathiesen JM, Shah ST, Lyons JA, Caffrey M, Gellman SH, Steyaert J, Skiniotis G, Weis WI, Sunahara RK, Kobilka BK (2011b) Crystal structure of the beta2 adrenergic receptor-Gs protein complex. Nature 477:549–555PubMedPubMedCentralCrossRefGoogle Scholar
  68. Ring AM, Manglik A, Kruse AC, Enos MD, Weis WI, Garcia KC, Kobilka BK (2013) Adrenaline-activated structure of beta2-adrenoceptor stabilized by an engineered nanobody. Nature 502:575–579PubMedPubMedCentralCrossRefGoogle Scholar
  69. Rodriguez D, Bello X, Gutierrez-de-Teran H (2012) Molecular modelling of G protein-coupled receptors through the web. Mol Inform 31:334–341PubMedCrossRefGoogle Scholar
  70. Rosenbaum DM, Zhang D, Lyons J, Holl R, Aragao D, Arlow DH, Rasmussen SGF, Choi H-J, Devree BT, Sunahara RK, Chae PS, Gellman SH, Dror RO, Shaw DE, Weis WI, Caffrey M, Gmeiner P, Kobilka BK (2011) Structure and function of an irreversible agonist-beta2 adrenoceptor complex. Nature 469:236–240PubMedPubMedCentralCrossRefGoogle Scholar
  71. Sandal M, Duy TP, Cona M, Zung H, Carloni P, Musiani F, Giorgetti A (2013) GOMoDo: a GPCRs online modeling and docking webserver. PLoS One 8:e74092PubMedPubMedCentralCrossRefGoogle Scholar
  72. Schneider EH, Seifert R (2016) Pharmacological characterization of human histamine receptors and histamine receptor mutants in the Sf9 cell expression system. Handb Exp Pharmacol. doi:10.1007/164_2016_124 Google Scholar
  73. Schneider EH, Schnell D, Papa D, Seifert R (2009) High constitutive activity and a G-protein-independent high-affinity state of the human histamine H(4)-receptor. Biochemistry 48:1424–1438PubMedCrossRefGoogle Scholar
  74. Schnell D, Seifert R (2010) Modulation of histamine H(3) receptor function by monovalent ions. Neurosci Lett 472:114–118PubMedCrossRefGoogle Scholar
  75. Schultes S, Nijmeijer S, Engelhardt H, Kooistra AJ, Vischer HF, de Esch IJP, Haaksma EEJ, Leurs R, de Graaf C (2013) Mapping histamine H4 receptor-ligand binding modes. Med Chem Commun 4:193–204CrossRefGoogle Scholar
  76. Seifert R, Wenzel-Seifert K, Bürckstümmer T, Pertz HH, Schunack W, Dove S, Buschauer A, Elz S (2003) Multiple differences in agonist and antagonist pharmacology between human and guinea-pig histamine H1-receptor. J Pharmacol Exp Ther 305:1104–1115PubMedCrossRefGoogle Scholar
  77. Seifert R, Strasser A, Schneider EH, Neumann D, Dove S, Buschauer A (2013) Molecular and cellular analysis of human histamine receptor subtypes. Trends Pharmacol Sci 34:33–58PubMedCrossRefGoogle Scholar
  78. Selent J, Sanz F, Pastor M, De Fabritiis G (2010) Induced effects of sodium ions on dopaminergic G-protein coupled receptors. PLoS Comput Biol 6(8) pii: e1000884Google Scholar
  79. Shimamura T, Shiroishi M, Weyand S, Tsujimoto H, Winter G, Katritch V, Abagyan R, Cherezov V, Liu W, Han GW, Kobayashi T, Stevens RC, Iwata S (2011) Structure of the human histamine H-1 receptor complex with doxepin. Nature 475:65–U82PubMedPubMedCentralCrossRefGoogle Scholar
  80. Shiroishi M, Kobayashi T (2016) Structural analysis of the histamine H1 receptor. Handb Exp Pharmacol. doi:10.1007/164_2016_10 PubMedGoogle Scholar
  81. Sirci F, Istyastono EP, Vischer HF, Kooistra AJ, Nijmeijer S, Kuijer M, Wijtmans M, Mannhold R, Leurs R, de Esch IJ, de Graaf C (2012) Virtual fragment screening: discovery of histamine H3 receptor ligands using ligand-based and protein-based molecular fingerprints. J Chem Inf Model 52:3308–3324PubMedCrossRefGoogle Scholar
  82. Smits RA, de Esch IJ, Zuiderveld OP, Broeker J, Sansuk K, Guaita E, Coruzzi G, Adami M, Haaksma E, Leurs R (2008a) Discovery of quinazolines as histamine H4 receptor inverse agonists using a scaffold hopping approach. J Med Chem 51:7855–7865PubMedCrossRefGoogle Scholar
  83. Smits RA, Lim HD, Hanzer A, Zuiderveld OP, Guaita E, Adami M, Coruzzi G, Leurs R, de Esch IJ (2008b) Fragment based design of new H4 receptor-ligands with anti-inflammatory properties in vivo. J Med Chem 51:2457–2467PubMedCrossRefGoogle Scholar
  84. Southan C (2016) Retrieving GPCR data from public databases. Curr Opin Pharmacol 30:38–43PubMedCrossRefGoogle Scholar
  85. Strasser A (2009) Molecular modeling and QSAR-based design of histamine receptor ligands. Expert Opin Drug Discovery 4:1061–1075CrossRefGoogle Scholar
  86. Strasser A, Wittmann HJ (2007) LigPath: a module for predictive calculation of a ligand’s pathway into a receptor-application to the gpH1-receptor. J Mol Model 13:209–218PubMedCrossRefGoogle Scholar
  87. Strasser A, Wittmann HJ (2010) 3D-QSAR CoMFA study to predict orientation of suprahistaprodifens and phenoprodifens in the binding-pocket of four histamine H1-receptor species. Mol Inform 29:333–341PubMedCrossRefGoogle Scholar
  88. Strasser A, Wittmann H-J (2013) Modelling of GPCRs—a practical handbook. Springer, DordrechtCrossRefGoogle Scholar
  89. Strasser A, Striegl B, Wittmann HJ, Seifert R (2008a) Pharmacological profile of histaprodifens at four recombinant H1-receptor species isoforms. J Pharmacol Exp Ther 324:60–71PubMedCrossRefGoogle Scholar
  90. Strasser A, Wittmann HJ, Seifert R (2008b) Ligand-specific contribution of the N terminus and E2-loop to pharmacological properties of the histamine H1-receptor. J Pharmacol Exp Ther 326:783–791PubMedCrossRefGoogle Scholar
  91. Strasser A, Wittmann HJ, Kunze M, Elz S, Seifert R (2009) Molecular basis for the selective interaction of synthetic agonists with the human histamine H1-receptor compared with the guinea pig H1-receptor. Mol Pharmacol 75:454–465PubMedCrossRefGoogle Scholar
  92. Strasser A, Wittmann H-J, Buschauer A, Schneider EH, Seifert R (2013) Species-dependent activities of GPCR ligands: lessons from histamine receptor orthologs. Trends Pharmacol Sci 34:13–32PubMedCrossRefGoogle Scholar
  93. Strasser A, Wittmann HJ, Schneider EH, Seifert R (2015) Modulation of GPCRs by monovalent cations and anions. Naunyn Schmiedebergs Arch Pharmacol 388:363–380PubMedCrossRefGoogle Scholar
  94. Tautermann CS, Seeliger D, Kriegel JM (2015) What can we learn from molecular dynamic simulations for GPCR drug design? Comput Struct Biotechnol J 13:111–121PubMedCrossRefGoogle Scholar
  95. ter Laak AM, Timmerman H, Leurs R, Nederkoorn PH, Smit MJ, Donne-Op den Kelder GM (1995) Modelling and mutation studies on the histamine H1-receptor agonist binding site reveal different binding modes for H1-agonists: Asp116 (TM3) has a constitutive role in receptor stimulation. J Comput Aided Mol Des 9:319–330PubMedCrossRefGoogle Scholar
  96. Thomas T, Fang Y, Yuriev E, Chalmers DK (2016) Ligand binding pathways of clozapine and haloperidol in the dopamine D2 and D3 receptors. J Chem Inf Model 56:308–321PubMedCrossRefGoogle Scholar
  97. Vass M, Kooistra AJ, Ritschel T, Leurs R, de Esch IJ, de Graaf C (2016) Molecular interaction fingerprint approaches for GPCR drug discovery. Curr Opin Pharmacol 30:59–68PubMedCrossRefGoogle Scholar
  98. Venkatakrishnan AJ, Deupi X, Lebon G, Tate CG, Schertler GFX, Babu MM (2013) Molecular signatures of G-protein-coupled receptors. Nature 494:185–194PubMedCrossRefGoogle Scholar
  99. Verma J, Khedkar VM, Coutinho EC (2010) 3D-QSAR in drug design—a review. Curr Top Med Chem 10:95–115PubMedCrossRefGoogle Scholar
  100. Wacker D, Fenalti G, Brown MA, Katritch V, Abagyan R, Cherezov V, Stevens RC (2010) Conserved binding mode of human beta2 adrenergic receptor inverse agonists and antagonist revealed by X-ray crystallography. J Am Chem Soc 132:11443–11445PubMedPubMedCentralCrossRefGoogle Scholar
  101. Wacker D, Wang C, Katritch V, Han GW, Huang XP, Vardy E, McCorvy JD, Jiang Y, Chu M, Siu FY, Liu W, Xu HE, Cherezov V, Roth BL, Stevens RC (2013) Structural features for functional selectivity at serotonin receptors. Science 340:615–619PubMedPubMedCentralCrossRefGoogle Scholar
  102. Wagner E, Wittmann HJ, Elz S, Strasser A (2011) Mepyramine-JNJ7777120-hybrid compounds show high affinity to hH(1)R, but low affinity to hH(4)R. Bioorg Med Chem Lett 21:6274–6280PubMedCrossRefGoogle Scholar
  103. Wang C, Jiang Y, Ma J, Wu H, Wacker D, Katritch V, Han GW, Liu W, Huang XP, Vardy E, McCorvy JD, Gao X, Zhou XE, Melcher K, Zhang C, Bai F, Yang H, Yang L, Jiang H, Roth BL, Cherezov V, Stevens RC, Xu HE (2013) Structural basis for molecular recognition at serotonin receptors. Science 340:610–614PubMedPubMedCentralCrossRefGoogle Scholar
  104. Warne T, Serrano-Vega MJ, Baker JG, Moukhametzianov R, Edwards PC, Henderson R, Leslie AG, Tate CG, Schertler GF (2008) Structure of a beta1-adrenergic G-protein-coupled receptor. Nature 454:486–491PubMedPubMedCentralCrossRefGoogle Scholar
  105. Warne T, Moukhametzianov R, Baker JG, Nehme R, Edwards PC, Leslie AG, Schertler GF, Tate CG (2011) The structural basis for agonist and partial agonist action on a beta(1)-adrenergic receptor. Nature 469:241–244PubMedPubMedCentralCrossRefGoogle Scholar
  106. Warne T, Edwards PC, Leslie AG, Tate CG (2012) Crystal structures of a stabilized beta1-adrenoceptor bound to the biased agonists bucindolol and carvedilol. Structure 20:841–849PubMedCrossRefGoogle Scholar
  107. Weichert D, Kruse AC, Manglik A, Hiller C, Zhang C, Hubner H, Kobilka BK, Gmeiner P (2014) Covalent agonists for studying G protein-coupled receptor activation. Proc Natl Acad Sci U S A 111:10744–10748PubMedPubMedCentralCrossRefGoogle Scholar
  108. Wifling D, Löffel K, Nordemann U, Strasser A, Bernhardt G, Dove S, Seifert R and Buschauer A (2015a) Molecular determinants for the high constitutive activity of the human histamine H4 receptor: functional studies on orthologues and mutants. Br J Pharmacol 172:785–798Google Scholar
  109. Wifling D, Bernhardt G, Dove S, Buschauer A (2015b) The extracellular loop 2 (ECL2) of the human histamine H4 receptor substantially contributes to ligand binding and constitutive activity. PLoS One 10:e0117185PubMedPubMedCentralCrossRefGoogle Scholar
  110. Wittmann HJ, Strasser A (2015) Binding pathway of histamine to the hH4R, observed by unconstrained molecular dynamics. Bioorg Med Chem Lett 25:1259–1268PubMedCrossRefGoogle Scholar
  111. Wittmann HJ, Elz S, Seifert R, Strasser A (2011) N (alpha)-methylated phenylhistamines exhibit affinity to the hH(4)R-a pharmacological and molecular modelling study. Naunyn Schmiedebergs Arch Pharmacol 384:287–299PubMedCrossRefGoogle Scholar
  112. Wittmann HJ, Seifert R, Strasser A (2014a) Mathematical analysis of the sodium sensitivity of the human histamine H3 receptor. In Silico Pharmacol 2:1PubMedPubMedCentralCrossRefGoogle Scholar
  113. Wittmann HJ, Seifert R, Strasser A (2014b) Sodium binding to hH3R and hH 4R—a molecular modeling study. J Mol Model 20:2394PubMedCrossRefGoogle Scholar
  114. Xu D, Zhang Y (2012) Ab initio protein structure assembly using continuous structure fragments and optimized knowledge-based force field. Proteins 80:1715–1735PubMedPubMedCentralCrossRefGoogle Scholar
  115. Yarnitzky T, Levit A, Niv MY (2010) Homology modeling of G-protein-coupled receptors with X-ray structures on the rise. Curr Opin Drug Discov Devel 13:317–325PubMedGoogle Scholar
  116. Yuan S, Vogel H, Filipek S (2011) The role of water and sodium ions in the activation of the μ-opioid receptor. Angew Chem Int Ed 52:10112–10115CrossRefGoogle Scholar
  117. Yuriev E, Holien J, Ramsland PA (2015) Improvements, trends, and new ideas in molecular docking: 2012-2013 in review. J Mol Recognit 28:581–604PubMedCrossRefGoogle Scholar
  118. Zhang J, Yang J, Jang R, Zhang Y (2015) GPCR-I-TASSER: a hybrid approach to G protein-coupled receptor structure modeling and the application to the human genome. Structure 23:1538–1549PubMedPubMedCentralCrossRefGoogle Scholar
  119. Zou Y, Weis WI, Kobilka BK (2012) N-terminal T4 lysozyme fusion facilitates crystallization of a G protein coupled receptor. PLoS One 7:e46039PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  1. 1.Department of Pharmaceutical/Medicinal Chemistry II, Institute of PharmacyUniversity of RegensburgRegensburgGermany

Personalised recommendations