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Ligand and structure-based methodologies for the prediction of the activity of G protein-coupled receptor ligands

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Summary

Accurate in silico models for the quantitative prediction of the activity of G protein-coupled receptor (GPCR) ligands would greatly facilitate the process of drug discovery and development. Several methodologies have been developed based on the properties of the ligands, the direct study of the receptor–ligand interactions, or a combination of both approaches. Ligand-based three-dimensional quantitative structure-activity relationships (3D-QSAR) techniques, not requiring knowledge of the receptor structure, have been historically the first to be applied to the prediction of the activity of GPCR ligands. They are generally endowed with robustness and good ranking ability; however they are highly dependent on training sets. Structure-based techniques generally do not provide the level of accuracy necessary to yield meaningful rankings when applied to GPCR homology models. However, they are essentially independent from training sets and have a sufficient level of accuracy to allow an effective discrimination between binders and nonbinders, thus qualifying as viable lead discovery tools. The combination of ligand and structure-based methodologies in the form of receptor-based 3D-QSAR and ligand and structure-based consensus models results in robust and accurate quantitative predictions. The contribution of the structure-based component to these combined approaches is expected to become more substantial and effective in the future, as more sophisticated scoring functions are developed and more detailed structural information on GPCRs is gathered.

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Abbreviations

3D:

Three-dimensional

GB:

Generalized Born

GPCR:

G protein coupled receptor

LIE:

Linear interaction energy

LRM:

Linear response method

MEP:

Molecular electrostatic potentials

QSAR:

Quantitative structure-activity relationships

PB:

Poisson-Boltzman

PLS:

Partial least square

SAR:

Structure-activity relationships

TM:

Transmembrane domain

References

  1. Pierce KL, Premont RT, Lefkowitz RJ (2002) Nat Rev Mol Cell Biol 3:639

    Article  CAS  Google Scholar 

  2. Overington JP, Al-Lazikani B, Hopkins AL (2006) Nat Rev Drug Discov 5:993

    Article  CAS  Google Scholar 

  3. Schertler GFX, Villa C, Henderson R (1993) Nature 362:770

    Article  CAS  Google Scholar 

  4. 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) Science 289:739

    Article  CAS  Google Scholar 

  5. Moro S, Spalluto G, Jacobson KA (2005) Trends Pharmacol Sci 26:44

    Article  CAS  Google Scholar 

  6. Costanzi S, Ivanov AA, Tikhonova IG, Jacobson KA (2007) In: Caldwell GW, Rahman AU, Player MR, Chouday MI (eds) Frontiers in drug design and discovery. Bentham, pp 63–79

  7. Costanzi S, Tikhonova IG, Ohno M, Roh EJ, Joshi BV, Colson AO, Houston D, Maddileti S, Harden TK, Jacobson KA (2007) J Med Chem 50:3229

    Article  CAS  Google Scholar 

  8. Patny A, Desai PV, Avery MA (2006) Curr Med Chem 13:1667

    Article  CAS  Google Scholar 

  9. Bissantz C, Schalon C, Guba W, Stahl M (2005) Proteins-Struct Func Bioinform 61:938

    Article  CAS  Google Scholar 

  10. Bissantz C, Bernard P, Hibert M, Rognan D (2003) Proteins-Struct Func Genet 50:5

    Article  CAS  Google Scholar 

  11. Evers A, Hessler G, Matter H, Klabunde T (2005) J Med Chem 48:5448

    Article  CAS  Google Scholar 

  12. Rasmussen SGF, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VRP, Sanishvili R, Fischetti RF, Schertler GF X, Weis WI, Kobilka BK (2007) Nature 450:383

    Article  CAS  Google Scholar 

  13. Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SGF, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC (2007) Science 318:1258

    Article  CAS  Google Scholar 

  14. Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SGF, Thian FS, Kobilka TS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK (2007) Science 318:1266

    Article  CAS  Google Scholar 

  15. Day PW, Rasmussen SGF, Parnot C, Fung JJ, Masood A, Kobilka TS, Yao XJ, Choi HJ, Weis WI, Rohrer DK, Kobilka BK (2007) Nat Methods 4:927

    Article  CAS  Google Scholar 

  16. Costanzi S (2008) J Med Chem. doi:10.1021/jm800044k

  17. Green SM, Marshall GR (1995) Trends Pharmacol Sci 16:285

    Article  CAS  Google Scholar 

  18. Holtje HD, Sippl W, Rognan D, Folkers G (2003) Molecular modeling. Basic principles and applications. Wiley-WCH, Weinheim

    Google Scholar 

  19. Cramer RD, Patterson DE, Bunce JD (1988) J Am Chem Soc 110:5959

    Article  CAS  Google Scholar 

  20. Wold S, Albano C, Dunn WJ, Esbensen K, Hellberg S, Johansson E, Lindberg W, Sjostrom M (1984) Analusis 12:477

    CAS  Google Scholar 

  21. Klebe G, Abraham U, Mietzner T (1994) J Med Chem 37:4130

    Article  CAS  Google Scholar 

  22. Greco G, Novellino E, Silipo C, Vittoria A (1991) Quant Struct-Act Relat 10:289

    Article  CAS  Google Scholar 

  23. Siddiqi SM, Pearlstein RA, Sanders LH, Jacobson KA (1995) Bioorg Med Chem 3:1331

    Article  CAS  Google Scholar 

  24. Moro S, van Rhee AM, Sanders LH, Jacobson KA (1998) J Med Chem 41:46

    Article  CAS  Google Scholar 

  25. Baraldi PG, Borea PA, Bergonzoni M, Cacciari B, Ongini E, Recanatini M, Spalluto G (1999) Drug Dev Res 46:126

    Article  CAS  Google Scholar 

  26. Li AH, Moro S, Forsyth N, Melman N, Ji XD, Jacobson KA (1999) J Med Chem 42:706

    Article  CAS  Google Scholar 

  27. Doytchinova I, Valkova I, Natcheva R (2001) Quant Struct-Act Relat 20:124

    Article  CAS  Google Scholar 

  28. Song YQ, Coupar IM, Iskander MN (2001) Quant Struct-Act Relat 20:23

    Article  CAS  Google Scholar 

  29. Rieger JM, Brown ML, Sullivan GW, Linden J, Macdonald TL (2001) J Med Chem 44:531

    Article  CAS  Google Scholar 

  30. Doytchinova I (2001) J Comput Aided Mol Des 15:29

    Article  CAS  Google Scholar 

  31. Jacobson KA, Moro S, Manthey JA, West PL, Ji XD (2002) Flavonoids Cell Funct 505:163

    CAS  Google Scholar 

  32. Doytchinova I, Valkova I, Natcheva R (2002) SAR QSAR Environ Res 13:227

    Article  CAS  Google Scholar 

  33. Bhattacharya P, Leonard JT, Roy K (2005) J Mol Model 11:516

    Article  CAS  Google Scholar 

  34. Fossa P, Pestarino M, Menozzi G, Mosti L, Schenone S, Ranise A, Bondavalli F, Trincavelli ML, Lucacchini A, Martini C (2005) Org Biomol Chem 3:2262

    Article  CAS  Google Scholar 

  35. Kim SK, Jacobson KA (2007) J Chem Inf Model 47:1225

    Article  CAS  Google Scholar 

  36. Moro S, Bacilieri M, Cacciari B, Spalluto G (2005) J Med Chem 48:5698

    Article  CAS  Google Scholar 

  37. Moro S, Braiuca P, Deflorian F, Ferrari C, Pastorin G, Cacciari B, Baraldi PG, Varani K, Borea PA, Spalluto G (2005) J Med Chem 48:152

    Article  CAS  Google Scholar 

  38. Goodford PJ (1985) J Med Chem 28:849

    Article  CAS  Google Scholar 

  39. Baroni M, Costantino G, Cruciani G, Riganelli D, Valigi R, Clementi S (1993) Quant Struct-Act Relat 12:9

    Article  CAS  Google Scholar 

  40. Balle T, Andersen K, Soby KK, Liljefors T (2003) J Mol Graph Model 21:523

    Article  CAS  Google Scholar 

  41. Brea J, Rodrigo J, Carrieri A, Sanz F, Cadavid MI, Enguix MJ, Villazon M, Mengod G, Caro Y, Masaguer CF, Ravina E, Centeno NB, Carotti A, Loza MI (2002) J Med Chem 45:54

    Article  CAS  Google Scholar 

  42. Broer BM, Gurrath M, Holtje HD (2003) J Comp-Aided Mol Des 17:739

    Article  Google Scholar 

  43. Audouze K, Nielsen EO, Peters D (2004) J Med Chem 47:3089

    Article  CAS  Google Scholar 

  44. Terzioglu N, Holtje D (2005) Collect Czech Chem Commun 70:1482

    Article  CAS  Google Scholar 

  45. Gasteiger J, Li XZ, Rudolph C, Sadowski J, Zupan J (1994) J Am Chem Soc 116:4608

    Article  CAS  Google Scholar 

  46. Wagener M, Sadowski J, Gasteiger J (1995) J Am Chem Soc 117:7769

    Article  CAS  Google Scholar 

  47. Moro S, Bacilieri M, Ferrari C, Spalluto G (2005) Curr Drug Discov Technol 2:13

    Article  CAS  Google Scholar 

  48. Moro S, Deflorian F, Bacilieri M, Spalluto G (2006) Curr Med Chem 13:639

    Article  CAS  Google Scholar 

  49. Moro S, Bacilieri M, Cacciari B, Bolcato C, Cusan C, Pastorin G, Klotz KN, Spalluto G (2006) Bioorg Med Chem 14:4923

    Article  CAS  Google Scholar 

  50. Tropsha A, Wang SX (2006) Ernst Schering Found Symp Proc 2:49

    Article  Google Scholar 

  51. Wang J, Dixon R, Kollman PA (1999) Proteins-Struct Func Genet 34:69

    Article  CAS  Google Scholar 

  52. Chipot C, Rozanska X, Dixit SB (2005) J Comput-Aided Mol Des 19:765

    Article  CAS  Google Scholar 

  53. Foloppe N, Hubbard R (2006) Curr Med Chem 13:3583

    Article  CAS  Google Scholar 

  54. Wang JY, Deng YQ, Roux B (2006) Biophys J 91:2798

    Article  CAS  Google Scholar 

  55. Henin J, Maigret B, Tarek M, Escrieut C, Fourmy D, Chipot C (2006) Biophys J 90:1232

    Article  CAS  Google Scholar 

  56. Aqvist J, Medina C, Samuelsson JE (1994) Protein Eng 7:385

    Article  CAS  Google Scholar 

  57. Hansson T, Marelius J, Aqvist J (1998) J Comput-Aided Mol Des 12:27

    Article  CAS  Google Scholar 

  58. JonesHertzog DK, Jorgensen WL (1997) J Med Chem 40:1539

    Article  CAS  Google Scholar 

  59. Carlsson J, Ander M, Nervall M, Aqvist J (2006) J Phys Chem B 110:12034

    Article  CAS  Google Scholar 

  60. Gutiérrez-de-Terán H, Pastor M, Centeno NB, Aqvist J, Sanz F (2004) Chembiochem 5:841

    Article  Google Scholar 

  61. Coupez B, Lewis RA (2006) Curr Med Chem 13:2995

    Article  CAS  Google Scholar 

  62. Konstantinou-Kirtay C, Mitchell JBO, Lumley JA (2007) Bmc Bioinformatics 8

  63. Gohlke H, Hendlich M, Klebe G (2000) J Mol Biol 295:337

    Article  CAS  Google Scholar 

  64. Ishchenko AV, Shakhnovich EI (2002) J Med Chem 45:2770

    Article  CAS  Google Scholar 

  65. Mitchell JBO, Laskowski RA, Alex A, Thornton JM (1999) J Comput Chem 20:1165

    Article  CAS  Google Scholar 

  66. Muegge I, Martin YC (1999) J Med Chem 42:791

    Article  CAS  Google Scholar 

  67. Cavasotto CN, Orry AJW, Abagyan RA (2003) Proteins-Struct Func Genet 51:423

    Article  CAS  Google Scholar 

  68. Jones G, Willett P, Glen RC (1995) J Mol Biol 245:43

    Article  CAS  Google Scholar 

  69. Kuntz ID (1992) Science 257:1078

    Article  CAS  Google Scholar 

  70. Rognan D, Lauemoller SL, Holm A, Buus S, Tschinke V (1999) J Med Chem 42:4650

    Article  CAS  Google Scholar 

  71. Wang RX, Liu L, Lai LH, Tang YQ (1998) J Mol Model 4:379

    Article  CAS  Google Scholar 

  72. Rarey M, Kramer B, Lengauer T, Klebe G (1996) J Mol Biol 261:470

    Article  CAS  Google Scholar 

  73. Vaidehi N, Schlyer S, Trabanino RJ, Floriano WB, Abrol R, Sharma S, Kochanny M, Koovakat S, Dunning L, Liang M, Fox JM, de Mendonca FL, Pease JE, Goddard WA, Horuk R (2006) J Biol Chem 281:27613

    Article  CAS  Google Scholar 

  74. Evers A, Klebe G (2004) J Med Chem 47:5381

    Article  CAS  Google Scholar 

  75. Becker OM, Marantz Y, Shacham S, Inbal B, Heifetz A, Kalid O, Bar-Haim S, Warshaviak D, Fichman M, Noiman S (2004) Proc Nat Acad Sci USA 101:11304

    Article  CAS  Google Scholar 

  76. Evers A, Klabunde T (2005) J Med Chem 48:1088

    Article  CAS  Google Scholar 

  77. Kellenberger E, Springael JY, Parmentier M, Hachet-Haas M, Galzi JL, Rognan D (2007) J Med Chem 50:1294

    Article  CAS  Google Scholar 

  78. Becker OM, Dhanoa DS, Marantz Y, Chen DL, Shacham S, Cheruku S, Heifetz A, Mohanty P, Fichman M, Sharadendu A, Nudelman R, Kauffman M, Noiman S (2006) J Med Chem 49:3116

    Article  CAS  Google Scholar 

  79. Chen JZ, Wang JM, Xie XQ (2007) J Chem Inform Model 47:1626

    Article  CAS  Google Scholar 

  80. Tikhonova IG, Sum CS, Neumann S, Engel S, Raaka BM, Costanzi S, Gershengorn MC (2008) J Med Chem 51:625

    Article  CAS  Google Scholar 

  81. Waller CL, Oprea TI, Giolitti A, Marshall GR (1993) J Med Chem 36:4152

    Article  CAS  Google Scholar 

  82. Depriest SA, Mayer D, Naylor CB, Marshall GR (1993) J Am Chem Soc 115:5372

    Article  CAS  Google Scholar 

  83. Warren GL, Andrews CW, Capelli AM, Clarke B, LaLonde J, Lambert MH, Lindvall M, Nevins N, Semus SF, Senger S, Tedesco G, Wall ID, Woolven JM, Peishoff CE, Head MS (2006) J Med Chem 49:5912

    Article  CAS  Google Scholar 

  84. Sippl W (2000) J Comput-Aided Mol Des 14:559

    Article  CAS  Google Scholar 

  85. Sippl W, Holtje HD (2000) J Mol Struct-Theochem 503:31

    Article  CAS  Google Scholar 

  86. Sippl W (2002) Bioorg Med Chem 10:3741

    Article  CAS  Google Scholar 

  87. Sippl W (2002) J Comput-Aided Mol Des 16:825

    Article  CAS  Google Scholar 

  88. Jojart B, Marki A (2007) J Mol Graph Model 25:711

    Article  CAS  Google Scholar 

  89. Li MY, Lu JF, Xia L (2005) Acta Chim Sinica 63:1875

    CAS  Google Scholar 

  90. Xu Y, Liu H, Niu CY, Luo C, Luo XM, Shen JH, Chen KX, Jiang HL (2004) Bioorg Med Chem 12:6193

    Article  CAS  Google Scholar 

  91. Iskander MN, Leung LM, Buley T, Ayad F, Di Iulio J, Tan YY, Coupar IM (2006) Eur J Med Chem 41:16

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank Dr. Santiago Vilar Varela for the helpful discussions. This research was supported by the Intramural Research Program of the NIH, NIDDK.

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Authors and Affiliations

  1. Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA

    Stefano Costanzi & Irina G. Tikhonova

  2. Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA

    T. Kendall Harden

  3. Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA

    Kenneth A. Jacobson

Authors
  1. Stefano Costanzi
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  2. Irina G. Tikhonova
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  3. T. Kendall Harden
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  4. Kenneth A. Jacobson
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Correspondence to Stefano Costanzi.

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Costanzi, S., Tikhonova, I.G., Harden, T.K. et al. Ligand and structure-based methodologies for the prediction of the activity of G protein-coupled receptor ligands. J Comput Aided Mol Des 23, 747–754 (2009). https://doi.org/10.1007/s10822-008-9218-3

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  • DOI: https://doi.org/10.1007/s10822-008-9218-3

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