Probing molecular interactions within class II MHC Aq/ glycopeptide/T-cell receptor complexes associated with collagen-induced arthritis

Journal of Medicinal Chemistry

Volumn 50, Issue 23, 2007, Pages 5627-5643

  Andersson, Ida E ^a   Dzhambazov, Balik ^b   Holmdahl, Rikard ^b   Linusson, Anna ^a   Kihlberg, Jan ^a,c  

^a UMEÅ UNIVERSITY   (Sweden)

^b LUND UNIVERSITY   (Sweden)

^c ASTRAZENECA R AND D   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE; COLLAGEN TYPE 2; GLYCINE; GLYCOPEPTIDE; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2AQ; T LYMPHOCYTE RECEPTOR; UNCLASSIFIED DRUG;

AMINO ACID SEQUENCE; AMINO TERMINAL SEQUENCE; ARTICLE; CARBON NUCLEAR MAGNETIC RESONANCE; CARBOXY TERMINAL SEQUENCE; CHEMICAL BOND; COCULTURE; COMPLEX FORMATION; CONTROLLED STUDY; DISEASE MODEL; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HUMAN; HUMAN CELL; HYBRIDOMA; MOLECULAR INTERACTION; MOLECULAR PROBE; PEPTIDE SYNTHESIS; PROTON NUCLEAR MAGNETIC RESONANCE; RHEUMATOID ARTHRITIS; SEQUENCE ANALYSIS; STRUCTURE ANALYSIS;

ALANINE; ANIMALS; ANTIGEN-PRESENTING CELLS; ARTHRITIS, EXPERIMENTAL; BINDING, COMPETITIVE; COCULTURE TECHNIQUES; COLLAGEN TYPE II; GLYCINE; GLYCOPEPTIDES; HISTOCOMPATIBILITY ANTIGENS CLASS II; HYBRIDOMAS; INTERLEUKIN-2; MICE; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PEPTIDE FRAGMENTS; PROTEIN BINDING; RATS; RECEPTORS, ANTIGEN, T-CELL; SPLEEN; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; T-LYMPHOCYTES;

EID: 36148963636     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0705410     Document Type: Article

References (88)

1. Arnett, F. C.; Edworthy, S. M.; Bloch, D. A.; McShane, D. J.; Fries, J. F.; Cooper, N. S.; Healey, L. A.; Kaplan, S. R.; Liang, M. H.; Luthra, H. S.; Medsger, T. A. Jr.; Mitchell, D. M.; Neustadt, D. H.; Pinals, R. S.; Schaller, J. G.; Sharp, J. T.; Wilder, R. L.; Hunder, G. G. The American Rheumatism Association 1987 Revised Criteria for the Classification of Rheumatoid Arthritis. Arthritis Rheum. 1988, 31, 315-324.
2. Astorga, G. P.; Williams, Jr, R. C. Altered Reactivity in Mixed Lymphocyte Culture of Lymphocytes from Patients with Rheumatoid Arthritis. Arthritis Rheum. 1969, 12, 547-554.
3. Stastny, P. Mixed Lymphocyte Cultures in Rheumatoid Arthritis. J. Clin. Invest. 1976, 57, 1148-1157.
4. Gregersen, P.; Silver, J.; Winchester, R. The Shared Epitope Hypothesis. An Approach to Understanding the Molecular Genetics of Susceptibility to Rheumatoid Arthritis. Arthritis Rheum. 1987, 30, 1205-1213.
5. McFarland, B. J.; Beeson, C. Binding Interactions Between Peptides and Proteins of the Class II Major Histocompatibility Complex. Med. Res. Rev. 2002, 22, 168-203.
6. Londei, M.; Savill, C. M.; Verhoef, A.; Brennan, F.; Leech, Z. A.; Duance, V.; Maini, R. N.; Feldmann, M. Persistence of Collagen Type II-Specific T-Cell Clones in the Synovial Membrane of a Patient with Rheumatoid Arthritis. Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 636-640.
7. Kim, H. Y.; Kim, W. U.; Cho, M. L.; Lee, S. K.; Youn, J.; Kim, S. I.; Yoo, W. H.; Park, J. H.; Min, J. K.; Lee, S. H.; Park, S. H.; Cho, C. S. Enhanced T Cell Proliferative Response to Type II Collagen and Synthetic Peptide CII (255-274) in Patients with Rheumatoid Arthritis. Arthritis Rheum. 1999, 42, 2085-2093.
8. Bäcklund, J.; Carlsen, S.; Höger, T.; Holm, B.; Fugger, L.; Kihlberg, J.; Burkhardt, H.; Holmdahl, R. Predominant Selection of T Cells Specific for the Glycosylated Collagen Type II Epitope (263-270) in Humanized Transgenic Mice and in Rheumatoid Arthritis. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 9960-9965.
9. Menzel, J.; Steffen, C.; Kolarz, G.; Eberl, R.; Frank, O.; Thumb, N. Demonstration of Antibodies to Collagen and of Collagen-Anticollagen Immune Complexes in Rheumatoid Arthritis Synovial Fluids. Ann. Rheum. Dis. 1976, 35, 446-450.
10. Cook, A. D.; Stockman, A.; Brand, C. A.; Tait, B. D.; Mackay, I. R.; Muirden, K. D.; Bernard, C. C. A.; Rowley, M. J. Antibodies to Type II Collagen and HLA Disease Susceptibility Markers in Rheumatoid Arthritis. Arthritis Rheum. 1999, 42, 2569-2576.
11. Burkhardt, H.; Koller, T.; Engström, Å.; Nandakumar, K. S.; Turnay, J.; Kraetsch, H. G.; Kalden, J. R.; Holmdahl, R. Epitope-Specific Recognition of Type II Collagen by Rheumatoid Arthritis Antibodies Is Shared With Recognition by Antibodies that are Arthritogenic in Collagen-Induced Arthritis in the Mouse. Arthritis Rheum. 2002, 46, 2339-2348.
12. Courtenay, J. S.; Dallman, M. J.; Dayan, A. D.; Martin, A.; Mosedale, B. Immunisation Against Heterologous Type II Collagen Induces Arthritis in Mice. Nature 1980, 283, 666-668.
13. Wooley, P. H.; Luthra, H. S.; Stuart, J. M.; David, C. S. Type II Collagen-Induced Arthritis in Mice. I. Major Histocompatibility Complex (I Region) Linkage and Antibody Correlates. J. Exp. Med. 1981, 154, 688-700.
14. Brunsberg, U.; Gustafsson, K.; Jansson, L.; Michaëlsson, E.; Ährlund-Richter, L.; Pettersson, S.; Mattsson, R.; Holmdahl, R. Expression of a Transgenic Class II Ab Gene Confers Susceptibility to Collagen-Induced Arthritis. Eur. J. Immunol. 1994, 24, 1698-1702.
15. Holm, B.; Bäcklund, J.; Recio, M. A. F.; Holmdahl, R.; Kihlberg, J. Glycopeptide Specificity of Helper T Cells Obtained in Mouse Models for Rheumatoid Arthritis. ChemBioChem 2002, 3, 1209-1222.
16. Rosloniec, E. F.; Whittington, K. B.; Brand, D. D.; Myers, L. K.; Stuart, J. M. Identification of MHC Class II and TCR Binding Residues in the Type II Collagen Immunodominant Determinant Mediating Collagen-Induced Arthritis. Cell. Immunol. 1996, 172, 21-28.
17. p Molecules. Eur. J. Immunol. 1998, 28, 755-767.
18. Michaëlsson, E.; Broddefalk, J.; Engström, Å.; Kihlberg, J.; Holmdahl, R. Antigen Processing and Presentation of a Naturally Glycosylated Protein Elicits Major Histocompatibility Complex Class II-Restricted, Carbohydrate-Specific T Cells. Eur. J. Immunol. 1996, 26, 1906-1910.
19. Broddefalk, J.; Bäcklund, J.; Almqvist, F.; Johansson, M.; Holmdahl, R.; Kihlberg, J. T Cells Recognize a Glycopeptide Derived from Type II Collagen in a Model for Rheumatoid Arthritis. J. Am. Chem. Soc. 1998, 120, 7676-7683.
20. Corthay, A.; Bäcklund, J.; Broddefalk, J.; Michaëlsson, E.; Goldschmidt, T. J.; Kihlberg, J.; Holmdahl, R. Epitope Glycosylation Plays a Critical Role for T Cell Recognition of Type II Collagen in Collagen-Induced Arthritis. Eur. J. Immunol. 1998, 28, 2580-2590.
21. Holm, B.; Baquer, S. M.; Holm, L.; Holmdahl, R.; Kihlberg, J. Role of the Galactosyl Moiety of Collagen Glycopeptides for T-Cell Stimulation in a Model for Rheumatoid Arthritis. Bioorg. Med. Chem. 2003, 11, 3981-3987.
22. Wellner, E.; Gustafsson, T.; Bäcklund, J.; Holmdahl, R.; Kihlberg, J. Synthesis of a C-Glycoside Analogue of β-D-Galactosyl Hydroxynorvaline and its Use in Immunological Studies. ChemBioChem 2000, 1, 272-280.
23. Marin, J.; Blaton, M. A.; Briand, J. P.; Chiocchia, G.; Fournier, C.; Guichard, G. Synthesis of Glycopeptides from Type II Collagen-Incorporating Galactosylated Hydroxylysine Mimetics and Their Use in Studying the Fine Specificity of Arthritogenic T Cells. ChemBioChem 2005, 6, 1796-1804.
24. Gustafsson, T.; Hedenström, M.; Kihlberg, J. Synthesis of a C-Glycoside Analogue of β-D-Galactosyl Hydroxylysine and Incorporation in a Glycopeptide from Type II Collagen. J. Org. Chem. 2006, 71, 1911-1919.
25. Holm, L.; Kjellén, P.; Holmdahl, R.; Kihlberg, J. Identification of the Minimal Glycopeptide Core Recognized by T Cells in a Model for Rheumatoid Arthritis. Bioorg. Med. Chem. 2005, 13, 473-482.
26. Holm, L.; Freeh, K.; Dzhambazov, B.; Holmdahl, R.; Kihlberg, J.; Linusson, A. Quantitative Structure-Activity Relationship of Peptides Binding to the Class II Major Histocompatibility Complex Molecule Ai Associated with Autoimmune Arthritis. J. Med. Chem. 2007, 50, 2049-2059.
27. Dzhambazov, B.; Nandakumar, K. S.; Kihlberg, J.; Fugger, L.; Holmdahl, R.; Vestberg, M. Therapeutic Vaccination of Active Arthritis with a Glycosylated Collagen Type II Peptide in Complex with MHC Class II Molecules. J. Immunol. 2006, 176, 1525-1533.
28. Bäcklund, J.; Treschow, A.; Bockermann, R.; Holm, B.; Holm, L.; Issazadeh-Navikas, S.; Kihlberg, J.; Holmdahl, R. Glycosylation of Type 11 Collagen is of Major Importance for T Cell Tolerance and Pathology in Collagen-Induced Arthritis. Eur. J. Immunol. 2002, 32, 3776-3784.
29. Rosloniec, E. F.; Brandstetter, T.; Leyer, S.; Schwaiger, F. W.; Nagy, Z. A. Second-Generation Peptidomimetic Inhibitors of Antigen Presentation Effectively Treat Autoimmune Diseases in HLA-DR-Transgenic Mouse Models. J. Autoimmunity 2006, 27, 182-195.
30. Sloan-Lancaster, J.; Allen, P. M. Altered Peptide Ligand-Induced Partial T Cell Activation. Annu. Rev. Immunol. 1996, 14, 1-27.
31. Smilek, D. E.; Wraith, D. C.; Hodgkinson, S.; Dwivedy, S.; Steinman, L.; McDevitt, H. O. A Single Amino Acid Change in a Myelin Basic Protein Peptide Confers the Capacity to Prevent Rather Than Induce Experimental Autoimmune Encephalomyelitis. Proc. Natl Acad. Sci. U.S.A. 1991, 88, 9633-9637.
32. Gautam, A. M.; Lock, C. B.; Smilek, D. E.; Pearson, C. I.; Steinman, L.; McDevitt, H. O. Minimum Structural Requirements for Peptide Presentation by Major Histocompatibility Complex Class II Molecules: Implications in Induction of Autoimmunity. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 767-771.
33. Hart, M.; Beeson, C. Utility of Azapeptides as Major Histocompatibility Complex Class II Protein Ligands for T-Cell Activation. J. Med. Chem. 2001, 44, 3700-3709.
34. Bolin, D. R.; Swain, A. L.; Sarabu, R.; Berthel, S. J.; Gillespie, P.; Huby, N. J. S.; Makofske, R.; Orzechowski, L.; Perrotta, A.; Toth, K.; Cooper, J. P.; Jiang, N.; Falcioni, F.; Campbell, R.; Cox, D.; Gaizband, D.; Belunis, C. J.; Vidovic, D.; Ito, K.; Crowther, R.; Kammlott, U.; Zhang, X.; Palermo, R.; Weber, D.; Guenot, J.; Nagy, Z.; Olson, G. L. Peptide and Peptide Mimetic Inhibitors of Antigen Presentation by HLA-DR Class II MHC Molecules. Design, Structure-Activity Relationships, and X-ray Crystal Structures. J. Med. Chem. 2000, 43, 2135-2148.
35. Mézière, C.; Viguier, M.; Dumortier, H.; Lo-Man, R.; Leclerc, C.; Guillet, J. G.; Briand, J. P.; Muller, S. In Vivo T Helper Cell Response to Retro-Inverso Peptidomimetics. J. Immunol. 1997, 159, 3230-3237.
36. Cotton, J.; Hervé, M.; Pouvelle, S.; Maillère, B.; Menez, A. Pseudopeptide Ligands for MHC II-Restricted T Cells. Int. Immunol. 1998, 10, 159-166.
37. Ettouati, L.; Salvi, J. P.; Trescol-Biémont, M. C.; Walchshofer, N.; Gerlier, D.; Rabourdin-Combe, C.; Paris, J. Substitution of Peptide Bond 53-54 of HEL(52-61) with an Ethylene Bond Rather Than Reduced Peptide Bond is Tolerated by an MHC-II Restricted T Cell. Pept. Res. 1996, 9, 248-253.
38. Ettouati, L.; Casimir, J. R.; Raynaud, I.; Trescol-Biémont, M. C.; Carrupt, P. A.; Gerlier, D.; Rabourdin-Combe, C.; Testa, B.; Paris, J. Synthesis, Biological Activity and Molecular Modelling of the 53-54 Ketomethylene Analogue of HEL(52-61). Protein Pept. Lett. 1998, 5, 221-229.
39. Smith, A. B., III.; Benowitz, A. B.; Sprengeler, P. A.; Barbosa, J.; Guzman, M. C.; Hirschmann, R.; Schweiger, E. J.; Bolin, D. R.; Nagy, Z.; Campbell, R. M.; Cox, D. C.; Olson, G. L. Design and Synthesis of a Competent Pyrrolinone-Peptide Hybrid Ligand for the Class II Major Histocompatibility Complex Protein HLA-DR1. J. Am. Chem. Soc. 1999, 121, 9286-9298.
40. Koehler, N. K. U.; Yang, C. Y.; Varady, J.; Lu, Y.; Wu, X.; Liu, M.; Yin, D.; Bartels, M.; Xu, B.; Roller, P. P.; Long, Y.; Li, P.; Kattah, M.; Cohn, M. L.; Moran, K.; Tilley, E.; Richert, J. R.; Wang, S. Structure-Based Discovery of Nonpeptidic Small Organic Compounds To Block the T Cell Response to Myelin Basic Protein. J. Med. Chem. 2004, 47, 4989-4997.
41. 2O]A1a Containing Analogue of the Drug Desmopressin. Bioorg. Med. Chem. Lett. 2002, 12, 841-844.
42. Holm, L.; Bockermann, R.; Wellner, E.; Bäcklund, J.; Holmdahl, R.; Kihlberg, J. Side-Chain and Backbone Amide Bond Requirements for Glycopeptide Stimulation of T-Cells Obtained in a Mouse Model for Rheumatoid Arthritis. Bioorg. Med. Chem. 2006, 14, 5921-5932.
43. Pietersz, G. A.; Pouniotis, D. S.; Apostolopoulos, V. Design of Peptide-Based Vaccines for Cancer. Curr. Med. Chem. 2006, 13, 1591-1607.
44. Korber, B.; LaBute, M.; Yusim, K. Immunoinformatics Comes of Age. PLoS Comput. Biol. 2006, 2, e71.
45. Davies, M. N.; Flower, D. R. Harnessing Bioinformatics to Discover New Vaccines. Drug Discovery Today 2007, 12, 389-395.
46. RCSB Protein Data Bank; http://www.rcsb.org/pdb/home/home.do (accessed September 18, 2006).
47. b Peptide-Binding Motif. J. Mol. Biol. 2003, 326, 1157-1174.
48. d-Peptide Complexes Reveal That High Affinity Can Be Achieved without Large Anchor Residues. Immunity 1998, 8, 319-329.
49. b. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 8820-8825.
50. 2]ASp. J. Org. Chem. 1996, 61, 2901-2903.
51. Våbenø, J.; Brisander, M.; Lejon, T.; Luthman, K. Diastereoselective Reduction of a Chiral N-Boc-Protected δ-Amino-α,β-unsaturated γ-Keto Ester Phe-Gly Dipeptidomimetic. J. Org. Chem. 2002, 67, 9186-9191.
52. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush, W. R.; Sakai, T. Horner-Wadsworth-Emmons Reaction: Use of Lithium Chloride and an Amine for Base-Sensitive Compounds. Tetrahedron Lett. 1984, 25, 2183-2186.
53. Våbenø, J.; Lejon, T.; Uhd Nielsen, C.; Steffansen, B.; Chen, W.; Ouyang, H.; Borchardt, R. T.; Luthman, K. Phe-Gly Dipeptidomimetics Designed for the Di-/Tripeptide Transporters PEPT1 and PEPT2: Synthesis and Biological Investigations. J. Med. Chem. 2004, 47, 1060-1069.
54. Dale, J. A.; Dull, D. L.; Mosher, H. S. α-Methoxy-α- trifluorometh-ylphenylacetic Acid, a Versatile Reagent for the Determination of Enantiomeric Composition of Alcohols and Amines. J. Org. Chem. 1969, 34, 2543-2549.
55. Boeijen, A.; van Ameijde, J.; Liskamp, R. M. J. Solid-Phase Synthesis of Oligourea Peptidomimetics Employing the Fmoc Protection Strategy. J. Org. Chem. 2001, 66, 8454-8462.
56. Kokotos, G. A Convenient One-Pot Conversion of N-Protected Amino-Acids and Peptides into Alcohols. Synthesis 1990, 4, 299-301.
57. Dess, D. B.; Martin, J. C. Readily Accessible 12-I-5 Oxidant for the Conversion of Primary and Secondary Alcohols to Aldehydes and Ketones. J. Org. Chem. 1983, 48, 4155-4156.
58. Lubell, W. D.; Rapoport, H. Configurational Stability of N-Protected α-Amino Aldehydes. J. Am. Chem. Soc 1987, 109, 236-239.
59. Myers, A. G.; Zhong, B.; Movassaghi, M.; Kung, D. W.; Lanman, B. A.; Kwon, S. Synthesis of Highly Epimerizable N-protected α-Amino Aldehydes of High Enantiomeric Excess. Tetrahedron Lett. 2000, 41, 1359-1362.
60. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination Procedures. J. Org. Chem. 1996, 61, 3849-3862.
61. Wiktelius, D.; Luthman, K. Taking Control of P1, P1′ and Double Bond Stereochemistry in the Synthesis of Phe-Phe (E)-Alkene Amide Isostere Dipeptidomimetics. Org. Biomol. Chem. 2007, 5, 603-605.
62. McDougal, P. G.; Rico, J. G.; Oh, Y. I.; Condon, B. D. A Convenient Procedure for the Monosilylation of Symmetric 1,n-Diols. J. Org. Chem. 1986, 51, 3388-3390.
63. Harnden, M. R.; Jarvest, R. L. Analogues of the Antiviral Acyclonucleoside 9-(4-Hydroxy-3-hydroxymethylbutyl)guanine. Part 4. Substitution on the 2-Amino Group. J. Chem. Soc., Perkin Trans. I 1989, 12, 2207-2213.
64. Barry, C. S.; Bushby, N.; Harding, J. R.; Willis, C. L. Stereoselective Synthesis of the Tetrahydropyran Core of Polycarvernoside A. Org. Lett. 2005, 7, 2683-2686.
65. Andersson, E. C.; Hansen, B. E.; Jacobsen, H.; Madsen, L. S.; Andersen, C. B.; Engberg, J.; Rothbard, J. B.; Sønderstrup McDevitt, G.; Malmström, V.; Holmdahl, R.; Svejgaard, A.; Fugger, L. Definition of MHC and T Cell Receptor Contacts in the HLA-DR4-Restricted Immunodominant Epitope in Type II Collagen and Characterization of Collagen-Induced Arthritis in HLA-DR4 and Human CD4 Transgenic Mice. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 7574-7579.
66. Syed, B. M.; Gustafsson, T.; Kihlberg, J. 9-BBN as a Convenient Protecting Group in Functionalisation of Hydroxylysine. Tetrahedron 2004, 60, 5571-5575.
67. González-Muñiz, R.; García-López, M. T.; Gómez-Monterrey, I.; Herranz, R.; Jimeno, M. L.; Suárez-Gea, M. L.; Johansen, N. L.; Madsen, K.; Thøgersen, H.; Suzdak, P. Ketomethylene and (Cyanomethylene)amino Pseudopeptide Analogues of the C-Terminal Hexapeptide of Neurotensin. J. Med. Chem. 1995, 38, 1015-1021.
68. The deacetylation of 28 and 31 was initially performed in a small test scale and was allowed to proceed for a longer period of time (2 h) with careful monitoring by analytical reversed-phase HPLC. It was found that the deacetylation was complete after approximately 10 min, displaying one major product peak corresponding to the desired glycopeptide and one smaller peak with a slightly different retention time. With increasing reaction time, the ratio between the two peaks approached, and finally reached, 1:1. After separation, both peaks were found to have the correct mass when analyzed with LCMS, indicating that a mixture of diastereomers resulting from racemization of the stereocenter in the isostere had been obtained.
69. McFarland, B. J.; Katz, J. F.; Sant, A. J.; Beeson, C. Energetics and Cooperativity of the Hydrogen Bonding and Anchor Interactions that Bind Peptides to MHC Class II Protein. J. Mol. Biol. 2005, 350, 170-183.
70. Jensen, T.; Nielsen, M.; Gad, M.; Hansen, P.; Komba, S.; Meldal, M.; Ødum, N.; Werdelin, O. Radically Altered T Cell Receptor Signaling in Glycopeptide-Specific T Cell Hybridoma Induced by Antigen with Minimal Differences in the Glycan Group. Eur. J. Immunol. 2001, 31, 3197-3206.
71. k Complexes: Correlation of the Dissociation Rate with T-Cell Reponsiveness. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 12862-12866.
72. Lyons, D. S.; Lieberman, S. A.; Hampl, J.; Boniface, J. J.; Chien, Y.; Berg, L. J.; Davis, M. M. A TCR Binds to Antagonist Ligands with Lower Affinities and Faster Dissociation Rates Than to Agonists. Immunity 1996, 5, 53-61.
73. Kersh, G. J.; Kersh, E. N.; Fremont, D. H.; Allen, P. M. High- and Low-Potency Ligands with Similar Affinities for the TCR: The Importance of Kinetics in TCR Signaling. Immunity 1998, 9, 817-826.
74. Molecular Operating Environment (MOE), version 2005.06; Chemical Computing Group Inc.: 1010 Sherbrooke St. West Suite, 910 Montreal, Canada H3A 2R7.
75. Swiss-Prot/TREMBL; http://www.expasy.org/sprot/ (accessed September 18, 2006).
76. Protein-protein BLAST; http://www.ncbi.nlm.nih.gov/BLAST/ (accessed September 18, 2006).
77. Word, J. M.; Lovell, S. C.; Richardson, J. S.; Richardson, D. C. Asparagine and Glutamine: Using Hydrogen Atom Contacts in the Choice of Side-Chain Amide Orientation. J. Mol. Biol. 1999, 285, 1735-1747.
78. BABEL, version 1.6; OpenEye Scientific Software Inc.: 3600 Cerrillos Road, Suite 1107, Santa Fe, NM 87507.
79. Weininger, D. SMILES, a Chemical Language and Information-System. I. Introduction to Methodology and Encoding Rules. J. Chem. Inf. Comput. Sci. 1988, 28, 31-36.
80. CORINA; Molecular Networks GmbH, Nägelsbachstaβe 25, 91052 Erlangen, Germany, http://www2.chemie.uni-erlangen.de/software/corina/ free_struct.html (accessed November 1, 2006).
81. OMEGA, version 2.0; OpenEye Scientific Software Inc.: 3600 Cerrillos Road, Suite 1107, Santa Fe, NM 87507.
82. FRED, version 2.0.1; OpenEye Scientific Software Inc.: 3600 Cerrillos Road, Suite 1107, Santa Fe, NM 87507.
83. Andersson, C. D.; Thysell, E.; Lindström, A.; Bylesjö, M.; Raubacher, F.; Linusson, A. A Multivariate Approach to Investigate Docking Parameters' Effects on Docking Performance. J. Chem. Inf. Model. 2007, 47, 1673-1687.
84. Kofron, W. G.; Baclawski, L. M. A Convenient Method for Estimation of Alkyllithium Concentrations. J. Org. Chem. 1976, 41, 1879-1880.
85. Bodanszky, M.; Bodanszky, A. Protecting Groups. In The Practice of Peptide Synthesis, 1st ed.; Hafner, K., Rees, C. W., Trost, B. M., Lehn, J. M., von Ragué Schleyer, P., Zahradnik, R., Eds.; Springer-Verlag: New York, 1984; Vol. 21, pp 20.
86. Brook, M. A.; Chan, T. H. A Simple Procedure for the Esterification of Carboxylic Acids. Synthesis 1983, 3, 201-203.
87. Krchnak, V.; Vagner, J.; Lebl, M. Noninvasive Continous Monitoring of Solid-Phase Peptide Synthesis by Acid-Base Indicator. Int. J. Pept. Prot. Res. 1988, 32, 415-416.
88. Kaiser, E.; Colescott, R. L.; Bossinger, C. D.; Cook, P. I. Color Test for Detection of Free Terminal Amino Groups in the Solid-Phase Synthesis of Peptides. Anal. Biochem. 1970, 34, 595-598.