Application of Bioinformatics Principles for Target Evaluation

  • Anthony Carvalloza
  • Mohammad Fallahi
  • Sahba Tabrizifard


In order to reduce time spent during the lead optimization phase of a drug discovery project, many researchers have attempted to incorporate computerized modeling approaches as part of their program. Various software tools have been developed in support of this pursuit. Molecular modeling, which attempts to produce an electronic representation for the structure of a molecule of interest, and docking, which attempts to discover which molecules are likely to bind to one another, are two approaches that have been used successfully. Although these approaches have worked best with static molecules, recently new tools have been developed to aid in working with more challenging targets, such as antibodies designed to interfere with the function of many cell surface receptors such as G protein-coupled receptors (GPCRs).


Therapeutic Antibody Complementarity Determine Region Docking Method Influenza Virus Hemagglutinin Antibody Sequence 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Agostino M, Jene C, Boyle T, Ramsland PA, Yuriev E (2009) Molecular docking of carbohydrate ligands to antibodies: structural validation against crystal structures. J Chem Inf Model 49:2749–2760PubMedCrossRefGoogle Scholar
  2. Arnold K, Bordoli L, Kopp J, Schwede T (2006) The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics 22:195–201PubMedCrossRefGoogle Scholar
  3. Breckpot K, Escors D (2009) Dendritic cells for active anti-cancer immunotherapy: targeting activation pathways through genetic modification. Endocr Metab Immune Disord Drug Targets 9:328–343PubMedGoogle Scholar
  4. Chen CR, McLachlan SM, Rapoport B (2007) Suppression of thyrotropin receptor constitutive activity by a monoclonal antibody with inverse agonist activity. Endocrinology 148:2375–2382PubMedCrossRefGoogle Scholar
  5. Chen R, Li L, Weng Z (2003) ZDOCK: An initial-stage protein-docking algorithm. Proteins: Struct Funct Bioinformatics 52:80–87CrossRefGoogle Scholar
  6. Comeau SR, Gatchell DW, Vajda S, Camacho CJ (2004) ClusPro: an automated docking and discrimination method for the prediction of protein complexes. Bioinformatics 20:45–50PubMedCrossRefGoogle Scholar
  7. Conn PJ, Christopoulos A, Lindsley CW (2009) Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov 8:41–54PubMedCrossRefGoogle Scholar
  8. Dorsam RT, Gutkind JS (2007) G-protein-coupled receptors and cancer. Nat Rev Cancer 7:79–94PubMedCrossRefGoogle Scholar
  9. Edmundson AB, Wood MK, Schiffer M, Hardman KD, Ainsworth CF, Ely KR, Deutsch HF (1970) A crystallographic investigation of a human IgG immunoglobulin. J Biol Chem 245:2763–2764PubMedGoogle Scholar
  10. Eglen RM, Reisine T (2009) New insights into GPCR function: implications for HTS. Methods Mol Biol 552:1–13PubMedCrossRefGoogle Scholar
  11. Elagoz A, Henderson D, Babu PS, Salter S, Grahames C, Bowers L, Roy MO, Laplante P, Grazzini E, Ahmad S, Lembo PM (2004) A truncated form of CKbeta8-1 is a potent agonist for human formyl peptide-receptor-like 1 receptor. Br J Pharmacol 141:37–46PubMedCrossRefGoogle Scholar
  12. Escolar G, Diaz-Ricart M, Gomez-Gil E, Serra M, Gasto C, Bozzo J, Galan AM (2005) Serotonergic mechanisms: a potential link between affective disorders and cardiovascular risk. Drugs Today (Barc) 41:721–743CrossRefGoogle Scholar
  13. Fujimoto A, Takatsuka S, Ishida I, Chiba J (2009) Production of human antibodies to native cytokine receptors using the genetic immunization of KM mice. Hum Antibodies 18:75–80PubMedGoogle Scholar
  14. Gomes I, Gupta A, Singh SP, Sharma SK (1999) Monoclonal antibody to the delta opioid receptor acts as an agonist in dual regulation of adenylate cyclase in NG108-15 cells. FEBS Lett 456:126–130PubMedCrossRefGoogle Scholar
  15. Graeler M, Shankar G, Goetzl EJ (2002) Cutting edge: suppression of T cell chemotaxis by sphingosine 1-phosphate. J Immunol 169:4084–4087PubMedGoogle Scholar
  16. Gray JJ, Moughan SE, Wang C, Schueler-Furman O, Kuhlman B, Rohl CA, Baker D (2003) Protein-protein docking with simultaneous optimization of rigid-body displacement and side-chain conformations. J Mol Biol 331(1):281–299PubMedCrossRefGoogle Scholar
  17. Gupta A, Devi LA (2006) The use of receptor-specific antibodies to study G-protein-coupled receptors. Mt Sinai J Med 73:673–681PubMedGoogle Scholar
  18. Gupta A, Heimann AS, Gomes I, Devi LA (2008) Antibodies against G-protein coupled receptors: novel uses in screening and drug development. Comb Chem High Throughput Screen 11:463–467PubMedCrossRefGoogle Scholar
  19. Harding PJ, Attrill H, Boehringer J, Ross S, Wadhams GH, Smith E, Armitage JP, Watts A (2009) Constitutive dimerization of the G-protein coupled receptor, neurotensin receptor 1, reconstituted into phospholipid bilayers. Biophys J 96:964–973PubMedCrossRefGoogle Scholar
  20. Hawlisch H, Frank R, Hennecke M, Baensch M, Sohns B, Arseniev L, Bautsch W, Kola A, Klos A, Kohl J (1998) Site-directed C3a receptor antibodies from phage display libraries. J Immunol 160:2947–2958PubMedGoogle Scholar
  21. Heilker R, Wolff M, Tautermann CS, Bieler M (2009) G-protein-coupled receptor-focused drug discovery using a target class platform approach. Drug Discov Today 14:231–240PubMedCrossRefGoogle Scholar
  22. Huang L, Sato AK, Sachdeva M, Fleming T, Townsend S, Dransfield DT (2005) Discovery of human antibodies against the C5aR target using phage display technology. J Mol Recognit 18:327–333PubMedCrossRefGoogle Scholar
  23. Hunter Z, Smyth HD, Durfee P, Chackerian B (2009) Induction of mucosal and systemic antibody responses against the HIV coreceptor CCR5 upon intramuscular immunization and aerosol delivery of a virus-like particle based vaccine. Vaccine 28:403–414PubMedCrossRefGoogle Scholar
  24. Hutchings CJ, Koglin M, Marshall FH (2010) Therapeutic antibodies directed at G protein-coupled receptors. MAbs 2:594–606PubMedCrossRefGoogle Scholar
  25. Jacoby E, Bouhelal R, Gerspacher M, Seuwen K (2006) The 7 TM G-protein-coupled receptor target family. Chem Med Chem 1:761–782PubMedGoogle Scholar
  26. Kaptein SJ, Jungscheleger-Russell J, Martinez–Martinez P, Beisser PS, Lavreysen H, Vanheel A, De Baets MH, Bruggeman CA, Vink C, Losen M (2008) Generation of polyclonal antibodies directed against G protein-coupled receptors using electroporation-aided DNA immunization. J Pharmacol Toxicol Methods 58:27–31PubMedCrossRefGoogle Scholar
  27. Lebesgue D, Wallukat G, Mijares A, Granier C, Argibay J, Hoebeke J (1998) An agonist-like monoclonal antibody against the human beta2-adrenoceptor. Eur J Pharmacol 348:123–133PubMedCrossRefGoogle Scholar
  28. Lensink MF, Méndez R, Wodak SJ (2007) Docking and scoring protein complexes: CAPRI, 3rd edn. Proteins: Struct Funct Bioinformatics 69:704–718CrossRefGoogle Scholar
  29. Li YY, Hou TJ, Goddard WA 3rd (2010) Computational modeling of structure-function of g protein-coupled receptors with applications for drug design. Curr Med Chem 17:1167–1180PubMedCrossRefGoogle Scholar
  30. Loisel TP, Ansanay H, St-Onge S, Gay B, Boulanger P, Strosberg AD, Marullo S, Bouvier M (1997) Recovery of homogeneous and functional beta 2-adrenergic receptors from extracellular baculovirus particles. Nat Biotechnol 15:1300–1304PubMedCrossRefGoogle Scholar
  31. Lyskov S, Gray JJ (2008) The RosettaDock server for local protein-protein docking. Nucleic Acids Res 36:(Web Server Issue):W233–W238PubMedCrossRefGoogle Scholar
  32. Magnani F, Shibata Y, Serrano-Vega MJ, Tate CG (2008) Co-evolving stability and conformational homogeneity of the human adenosine A2a receptor. Proc Natl Acad Sci USA 105:10744–10749PubMedCrossRefGoogle Scholar
  33. Marcatili P, Rosi A, Tramontano A (2008) PIGS: automatic prediction of antibody structures. Bioinformatics 24:1953–1954PubMedCrossRefGoogle Scholar
  34. Misumi S, Nakayama D, Kusaba M, Iiboshi T, Mukai R, Tachibana K, Nakasone T, Umeda M, Shibata H, Endo M et al (2006) Effects of immunization with CCR5-based cycloimmunogen on simian/HIVSF162P3 challenge. J Immunol 176:463–471PubMedGoogle Scholar
  35. Ohno Y, Suda K, Masuko K, Yagi H, Hashimoto Y, Masuko T (2008) Production and characterization of highly tumor-specific rat monoclonal antibodies recognizing the extracellular domain of human L-type amino-acid transporter 1. Cancer Sci 99:1000–1007PubMedCrossRefGoogle Scholar
  36. Pedotti M, Simonelli L, Livoti E, Varani L (2011) Computational docking of antibody-antigen complexes, opportunities and pitfalls illustrated by influenza hemagglutinin. Int J Mol Sci 12:226–251PubMedCrossRefGoogle Scholar
  37. Pin JP, Kniazeff J, Goudet C, Bessis AS, Liu J, Galvez T, Acher F, Rondard P, Prezeau L (2004) The activation mechanism of class-C G-protein coupled receptors. Biol Cell 96:335–342PubMedGoogle Scholar
  38. Robertson N, Jazayeri A, Errey J, Baig A, Hurrell E, Zhukov A, Langmead CJ, Weir M, Marshall FH (2011) The properties of thermostabilised G protein-coupled receptors (StaRs) and their use in drug discovery. Neuropharmacology 60:36–44PubMedCrossRefGoogle Scholar
  39. Rozec B, Gauthier C (2006) beta3-adrenoceptors in the cardiovascular system: putative roles in human pathologies. Pharmacol Ther 111:652–673PubMedCrossRefGoogle Scholar
  40. Schwede T, Sali A, Honig B, Levitt M, Berman HM, Jones D, Brenner SE, Burley SK, Das R, Dokholyan NV et al (2009) Outcome of a workshop on applications of protein models in biomedical research. Structure (London, England, 1993) 17:151–159Google Scholar
  41. Serrano-Vega MJ, Magnani F, Shibata Y, Tate CG (2008) Conformational thermostabilization of the beta1-adrenergic receptor in a detergent-resistant form. Proc Natl Acad Sci USA 105:877–882PubMedCrossRefGoogle Scholar
  42. Shibata Y, White JF, Serrano-Vega MJ, Magnani F, Aloia AL, Grisshammer R, Tate CG (2009) Thermostabilization of the neurotensin receptor NTS1. J Mol Biol 390:262–277PubMedCrossRefGoogle Scholar
  43. Sircar A, Gray JJ (2010) SnugDock: paratope structural optimization during antibody-antigen docking compensates for errors in antibody homology models. PLoS Comput Biol 6:e1000644PubMedCrossRefGoogle Scholar
  44. Sircar A, Kim ET, Gray JJ (2009) RosettaAntibody: antibody variable region homology modeling server. Nucleic Acids Res 37(Web Server Issue):W474–W479 PubMedCrossRefGoogle Scholar
  45. Smith NJ, Luttrell LM (2006) Signal switching, crosstalk, and arrestin scaffolds: novel G protein-coupled receptor signaling in cardiovascular disease. Hypertension 48:173–179PubMedCrossRefGoogle Scholar
  46. Sommerfelt MA (2009) Circular CCR5 peptide conjugates and uses thereof (WO2008074895). Expert Opin Ther Pat 19:1323–1328PubMedCrossRefGoogle Scholar
  47. Tovchigrechko A, Vakser IA (2006) GRAMM-X public web server for protein–protein docking. Nucleic Acids Res 34:W310–W314PubMedCrossRefGoogle Scholar
  48. Volante M, Bozzalla-Cassione F, Papotti M (2004) Somatostatin receptors and their interest in diagnostic pathology. Endocr Pathol 15:275–291PubMedCrossRefGoogle Scholar
  49. Whitelegg NRJ, Rees AR (2000) WAM: an improved algorithm for modelling antibodies on the WEB. Protein Eng 13:819–824PubMedCrossRefGoogle Scholar
  50. Worn A, Auf der Maur A, Escher D, Honegger A, Barberis A, Pluckthun A (2000) Correlation between in vitro stability and in vivo performance of anti-GCN4 intrabodies as cytoplasmic inhibitors. J Biol Chem 275:2795–2803PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Anthony Carvalloza
    • 1
  • Mohammad Fallahi
    • 1
  • Sahba Tabrizifard
    • 1
  1. 1.Scripps FloridaThe Scripps Research InstituteJupiterUSA

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