GPCR 3D homology models for ligand screening: Lessons learned from blind predictions of adenosine A2a receptor complex

Proteins: Structure, Function and Bioinformatics

Volumn 78, Issue 1, 2010, Pages 197-211

  Katritch, Vsevolod ^a,b   Rueda, Manuel ^b   Lam, Polo Chun Hung ^a   Yeager, Mark ^b,c   Abagyan, Ruben ^b  

^a MOLSOFT LLC   (United States)

^b SCRIPPS RESEARCH INSTITUTE   (United States)

^c UNIVERSITY OF VIRGINIA   (United States)

Author keywords

Adenosine receptor; Antagonist; Flexible docking; G protein; Gpcr structure; Homology model; Ligand guided optimization; Normal mode analysis; Subtype selectivity; Virtual screening

Indexed keywords

4 [2 [7 AMINO 2 (2 FURYL) 1,2,4 TRIAZOLO[2,3 A][1,3,5]TRIAZIN 5 YLAMINO]ETHYL]PHENOL; ADENOSINE A2A RECEPTOR; ADENOSINE A2A RECEPTOR ANTAGONIST; G PROTEIN COUPLED RECEPTOR; LIGAND;

AB INITIO CALCULATION; ARTICLE; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG RECEPTOR BINDING; HYDROPHOBICITY; LIGAND BINDING; MOLECULAR DOCKING; MUTAGENESIS; NUCLEOTIDE SEQUENCE; PREDICTION; PRIORITY JOURNAL; SEQUENCE HOMOLOGY; STRUCTURE ACTIVITY RELATION; AMINO ACID SEQUENCE; BINDING SITE; CHEMICAL STRUCTURE; CHEMISTRY; DRUG ANTAGONISM; DRUG POTENTIATION; HUMAN; METABOLISM; MOLECULAR GENETICS; PROTEIN BINDING; SEQUENCE ALIGNMENT; STRUCTURAL HOMOLOGY;

AMINO ACID SEQUENCE; BINDING SITES; DRUG DESIGN; HUMANS; LIGANDS; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; PROTEIN BINDING; RECEPTOR, ADENOSINE A2A; SEQUENCE ALIGNMENT; STRUCTURAL HOMOLOGY, PROTEIN;

EID: 77649196223     PISSN: 08873585     EISSN: 10970134     Source Type: Journal    
DOI: 10.1002/prot.22507     Document Type: Article

References (51)

1. Reynolds K, Abagyan R, Katritch V. 3d structure and modeling of GPCRs: implications for drug discovery. In: Gilchrist A, editor. Shifting paradigms in G protein coupled receptors. Hoboken, NJ: Wiley, in press.
2. Tyndall JD, Sandilya R. GPCR agonists and antagonists in the clinic. Med Chem 2005; 1: 405-421.
3. Lagerstrom MC, Schioth HB. Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov 2008; 7: 339-357.
4. Jacoby E, Bouhelal R, Gerspacher M, Seuwen K. The 7 TM G-protein-coupled receptor target family. Chem Med Chem 2006; 1: 761-782.
5. 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. Crystal structure of rhodopsin: a G protein-coupled receptor. Science 2000 289: 739-745. (Pubitemid 30650186)
6. Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC. High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science 2007 318: 1258-1265. (Pubitemid 350172884)
7. Rosenbaum. DM, Cherezov V, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK. GPCR engineering yields high-resolution structural, insights into beta2-adrenergic receptor function. Science 2007 318: 1266-1273. (Pubitemid 350172885)
8. Warne T, Serrano-Vega MJ, Baker JG, Moukhametzianov R, Edwards PC, Henderson R, Leslie AG, Tate CG, Schertler GF. Structure of a. beta(1) -adrenergic G-protein-coupled receptor. Nature 2008; 454: 486-491.
9. Jaakola VP, Griffith MT, Hanson MA, Cherezov V, Chien EY, Lane JR, Ijzerman AP, Stevens RC. The 2.6 angstrom crystal structure of a human A.2A adenosine receptor bound to an antagonist. Science 2008; 322: 1211-1217.
10. Katritch V, Reynolds KA, Cherezov V, Hanson MA, Roth CB, Yeager M, Abagyan R. Analysis of full and partial agonists binding to beta(2)-adrenergic receptor suggests a role of transmembrane helix V in agonist-specific conformational changes, J Mol Recognit 2009; 22: 307-318.
11. Reynolds KA, Katritch V, Abagyan R. Identifying conformational changes of the beta(2) adrenoceptor that enable accurate prediction of ligand/receptor interactions and screening for GPCR modulators. J Comput Aided Mol Des 2009; 23: 273-288.
12. de Graaf C, Rognan D. Selective structure-based virtual screening for Ml and partial agonists of the beta2 adrenergic receptor. J Med Chem 2008; 51: 4978-4985.
13. Kobilka B, Schertler GF. New G-protein-coupled receptor crystal structures: insights and limitations. Trends Pharmacol Sci 2008; 29: 79-83.
14. Hanson MA, Stevens RC. Discovery of new GPCR biology: one receptor structure at a time. Structure 2009; 17: 8-14.
15. Fedorov O, Sundstrom M, Marsden B, Knapp S. Insights for the development of specific kinase inhibitors by targeted structural genomics. Drug Discov Today 2007 12: 365-372. (Pubitemid 46636375)
16. Bissantz C, Logean A, Rognan D. High-throughput modeling of human G-protein coupled receptors: amino acid sequence alignment, three-dimensional model building, and receptor library screening. J Chem Inf Comput Sci 2004; 44: 1162-1176.
17. Zhang Y, Devries ME, Skolnick J. Structure modeling of all identified G protein-coupled receptors in the human genome. PLoS Comput Biol 2006; 2: e13.
18. Li Y, Goddard WA, III. Prediction of structure of G-protein coupled receptors and of bound ligands, with applications for drug design. Pac Symp Biocomput 2008; 13: 344-353.
19. Michino M, Abola E, Brooks III CL, Dixon JS, Moult J, Stevens RC. Critical assessment of GPCR structure modeling and docking 2008. Nat Rev: Drug Discovery 2009; 8: 455-463.
20. Lensink MP, Mendez R, Wodak SJ. Docking and scoring protein complexes: CAPRI, 3rd ed. Proteins 2007 69: 704-718. (Pubitemid 350214359)
21. Moult J, Fidelis K, Kryshtafovych A, Rost B, Hubbard T, Tramontano A. Critical assessment of methods of protein structure prediction-Round VII. Proteins 2007 69 (Suppl 8): 3-9. (Pubitemid 350210108)
22. Kim SK, Gao ZG, Van Rompaey P, Gross AS, Chen A, Van Calenbergh S, Jacobson KA. Modeling the adenosine receptors: comparison of the binding domains of A2.A agonists and antagonists. J Med Chem 2003 46: 4847-4859. (Pubitemid 37352025)
23. Cacciari B, Bolcato C, Spalluto G, Klotz KN, Bacilieri M, Deflorian F, Moro S. Pyrazolo-triazolopyrimidines as adenosine receptor antagonists: a complete structure-activity profile. Purinergic Signal 2007; 3: 183-193.
24. de Graaf C, Foata N, Engkvist O, Rognan D. Molecular modeling of the second extracellular loop of G-protein coupled receptors and its implication on structure-based virtual screening. Proteins 2008 71: 599-620. (Pubitemid 351430001)
25. Michielan L, Bacilieri M, Schiesaro A, Bolcato C, Pastorin G, Spalluto G, Cacciari B, Klotz KN, Kaseda C, Moro S. Linear and nonlinear 3D-QSAR approaches in tandem with ligand-based homology modeling as a computational strategy to depict the pyrazolo-triazolo-pyrimidine antagonists binding site of the human adenosine A2A receptor. J Chem Inf Model 2008 48: 350-363. (Pubitemid 351473038)
26. Schapira M., Abagyan R, Totrov M. Nuclear hormone receptor targeted, virtual screening. J Med. Chem 2003 46: 3045-3059. (Pubitemid 36775926)
27. Bisson WH, Cheltsov AV, Bruey-Seda.no N, Lin B, Chen J, Goldberger N, May LT, Christopoulos A, Dalton JT, Sexton PM, Zhang XK, Abagyan R. Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs. Proc Natl Acad Sci USA 2007; 104: 11927-11932.
28. Chen JZ, Wang J, Xie XQ. GPCR structure-based virtual screening approach for CB2 antagonist search. J Chem Inf Model 2007 47: 1626-1637. (Pubitemid 47210066)
29. Evers A, Klebe G. Successful virtual screening for a submicromolar antagonist of the neurokinin-1 receptor based on a ligand-supported homology model. J Med Chem 2004 47: 5381-5392. (Pubitemid 39382788)
30. Evers A, Klabunde T. Structure-based drug discovery using GPCR homology modeling: successful virtual screening for antagonists of the alphal A adrenergic receptor. J Med Chem 2005 48: 1088-1097. (Pubitemid 40270452)
31. Varady J, Wu X, Fang X, Min J, Hu Z, Levant B, Wang S. Molecular modeling of the threedimensional structure of dopamine 3 (D3) subtype receptor: discovery of novel and potent D3 ligands through a hybrid pharmacophore- and structure-based database searching approach. J Med Chem 2003; 46: 4377-4392.
32. Cavasotto CN, Orry AJ, Murgolo NJ, Czarniecki MF, Kocsi SA, Hawes BE, O'Neill KA, Hine H, Burton MS, Voigt JH, Abagyan RA, Bayne ML, Monsma FJ, Jr. Discovery of novel chemotypes to a G-protein-coupled receptor through ligand-steered homology modeling and structure-based virtual screening. J Med Chem 2008 51: 581-588. (Pubitemid 351252286)
33. Rueda M, Bottegoni G, Abagyan R. Consistent improvement of cross-docking results using binding site ensembles generated with elastic network normal modes. J Chem. Inf Model 2009; 49: 716-725.
34. Okuno Y, Tamon A, Yabuuchi H, Niijima S, Minowa Y, Tonomura K, Kunimoto R, Feng C. GLIDA: GPCR-ligand database for chemical genomics drug discovery-database and tools update. Nucleic Acids Res 2008 36 (Database issue) :D907-D912. (Pubitemid 351149843)
35. Read RJ, Chavali. G. Assessment of CASP7 predictions in the high accuracy template-based modeling category. Proteins 2007 69 (Suppl 8) 27-37. (Pubitemid 350210111)
36. Cardozo T, Totrov M, Abagyan R. Homology modeling by the ICM method. Proteins 1995; 23: 403-414.
37. Abagyan RA, Batalov S. Do aligned sequences share the same fold? J Mol Biol 1997; 273: 355-368.
38. Ballesteros JA, Weinstein H. Integrated methods for the construction of three dimensional models and computational probing of structure-function relations in G-protein coupled receptors. Methods Neurosa 1995; 25: 366-428.
39. Tirion MM. Large amplitude elastic motions in proteins from a single-parameter, atomic analysis. Phys Rev Lett 1996; 77: 1905-1908.
40. An J, Totrov M, Abagyan R. Pocketome via comprehensive identification and classification of ligand binding envelopes. Mol Cell Proteomics 2005; 4: 752-761.
41. Totrov M, Abagyan R. Flexible protein-ligand docking by global energy optimization in internal coordinates. Proteins 1997 29 (Suppl 1): 215-220. (Pubitemid 28090502)
42. Truchon JF, Bayly CL Evaluating virtual screening methods: good and bad metrics for the "early recognition" problem. J Chem Inf Model 2007; 47: 488-508.
43. Böhm. H-J, Brode S, Hesse U, Klebe G. Oxygen and nitrogen in competitive situations: which is the hydrogen-bond acceptor? G. Chem Eur J 1996; 2: 1509-1513.
44. Kubinyi H. Drug research: myths, hype and reality. Nat Rev Drug Discov 2003 2: 665-668. (Pubitemid 37368830)
45. Kim J, Jiang Q, Glashofer M, Yehle S, Wess J, Jacobson KA. Glutamate residues in the second extracellular loop of the human A2a adenosine receptor are required for ligand recognition. Mol Pharmacol 1996; 49: 683-691.
46. DeWeese-Scott C, Moult J. Molecular modeling of protein function regions. Proteins 2004 55: 942-961. (Pubitemid 38702952)
47. Cavasotto CN, Orry AJ. Ligand docking and structure-based virtual screening in drug discovery. Curr Top Med Chem 2007 7: 1006-1014. (Pubitemid 47040528)
48. Jacobson KA, Gao ZG. Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 2006; 5: 247-264.
49. Bottegoni G, Kufareva I, Totrov M, Abagyan R. Four-dimensional docking: a fast and accurate account of discrete receptor flexibility in ligand docking. J Med Chem. 2009; 52: 397-406.
50. Abagyan RA, Totrov MM. Contact area difference (CAD): a robust measure to evaluate accuracy of protein models. J Mol Biol 1997; 268: 678-685.
51. Cristalli G, Lambertucci C, Marucci G, Volpini R, Dal Ben D. A2A adenosine receptor and its modulators: overview on a druggabie GPCR and on structure-activity relationship analysis and binding requirements of agonists and antagonists. Curr Pharm Des 2008 14: 1525-1552. (Pubitemid 351997817)