Protein-protein interaction inhibition (2P2I): Mixed methodologies for the acceleration of lead discovery

In silico Lead Discovery

Volumn , Issue , 2011, Pages 118-143

  Roche, Philippe ^a,b   Morelli, Xavier ^a,b  

^a AIX MARSEILLE UNIVERSITY   (France)

^b CNRS Laboratoire Interactions et Modulateurs de Réponses   (France)

Author keywords

2P2I; Drug design; Druggable target.; Inhibitor; PPIs; Protein protein interactions; Protein protein interfaces; Small molecule; Structural databases

Indexed keywords

EID: 84884450737     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.2174/978160805142711101010118     Document Type: Editorial

References (181)

1. Overington, J.P.; Al-Lazikani, B.; Hopkins, A.L. How many drug targets are there? Nat. Rev. Drug Discov., 2006, 5, 993-996.
2. Wells, J.A.; McClendon, C.L. Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature., 2007, 450, 1001-1009.
3. Pagliaro, L.; Felding, J.; Audouze, K.; Nielsen, S.J.; Terry, R.B.; Krog-Jensen, C.; Butcher, S. Emerging classes of proteinprotein interaction inhibitors and new tools for their development. Curr. Opin. Chem. Biol., 2004, 8, 442-449.
4. Arkin, M.R.; Whitty, A. The road less traveled: modulating signal transduction enzymes by inhibiting their protein-protein interactions. Curr. Opin. Chem. Biol., 2009, 13, 284-290.
5. Berg, T. Small-molecule inhibitors of protein-protein interactions. Curr. Opin. Drug Discov. Devel., 2008, 11, 666-674.
6. Fry, D.C. Drug-like inhibitors of protein-protein interactions: a structural examination of effective protein mimicry. Curr. Protein Pept. Sci., 2008, 9, 240-247.
7. Dömling, A. Small molecular weight protein-protein interaction antagonists: an insurmountable challenge? Curr. Opin. Chem. Biol., 2008, 12, 281-291.
8. Villoutreix, B.O.; Bastard, K.; Sperandio, O.; Fahraeus, R.; Poyet, J.; Calvo, F.; Déprez, B.; Miteva, M.A. In silico-in vitro screening of protein-protein interactions: towards the next generation of therapeutics. Curr. Pharm. Biotechnol., 2008, 9, 103-122.
9. Patel, S.; Player, M.R. Small-molecule inhibitors of the p53-hdm2 interaction for the treatment of cancer. Expert Opin. Investig. Drugs., 2008, 17, 1865-1882.
10. Toogood, P.L. Inhibition of protein-protein association by small molecules: approaches and progress. J. Med. Chem., 2002, 45, 1543-1558.
11. Wells, J.A. Structural and functional epitopes in the growth hormone receptor complex. Biotechnology (N.Y.)., 1995, 13, 647-651.
12. Bahadur, R.P.; Zacharias, M. The interface of protein-protein complexes: analysis of contacts and prediction of interactions. Cell. Mol. Life Sci., 2008, 65, 1059-1072.
13. Jones, S.; Thornton, J.M. Principles of protein-protein interactions. Proc. Natl. Acad. Sci. U.S.A., 1996, 93, 13-20.
14. Lo Conte, L.; Chothia, C.; Janin, J. The atomic structure of protein-protein recognition sites. J. Mol. Biol., 1999, 285, 2177-2198.
15. Smith, R.D.; Hu, L.; Falkner, J.A.; Benson, M.L.; Nerothin, J.P.; Carlson, H.A. Exploring protein-ligand recognition with binding moad. J. Mol. Graph. Model., 2006, 24, 414-425.
16. Cheng, A.C.; Coleman, R.G.; Smyth, K.T.; Cao, Q.; Soulard, P.; Caffrey, D.R.; Salzberg, A.C.; Huang, E.S. Structurebased maximal affinity model predicts small-molecule druggability. Nat. Biotechnol., 2007, 25, 71-75.
17. Bahadur, R.P.; Chakrabarti, P.; Rodier, F.; Janin, J. A dissection of specific and non-specific protein-protein interfaces. J. Mol. Biol., 2004, 336, 943-955.
18. Tse, C.; Shoemaker, A.R.; Adickes, J.; Anderson, M.G.; Chen, J.; Jin, S.; Johnson, E.F.; Marsh, K.C.; Mitten, M.J.; Nimmer, P.; Roberts, L.; Tahir, S.K.; Xiao, Y.; Yang, X.; Zhang, H.; Fesik, S.; Rosenberg, S.H.; Elmore, S.W. Abt-263: a potent and orally bioavailable bcl-2 family inhibitor. Cancer Res., 2008, 68, 3421-3428.
19. Bahadur, R.P.; Chakrabarti, P.; Rodier, F.; Janin, J. Dissecting subunit interfaces in homodimeric proteins. Proteins., 2003, 53, 708-719.
20. Ofran, Y.; Rost, B. Protein-protein interaction hotspots carved into sequences. PLoS Comput. Biol., 2007, 3, e119.
21. Bogan, A.A.; Thorn, K.S. Anatomy of hot spots in protein interfaces. J. Mol. Biol., 1998, 280, 1-9.
22. Ma, B.; Nussinov, R. Trp/met/phe hot spots in protein-protein interactions: potential targets in drug design. Curr. Top. Med. Chem., 2007, 7, 999-1005.
23. Rickert, M.; Wang, X.; Boulanger, M.J.; Goriatcheva, N.; Garcia, K.C. The structure of interleukin-2 complexed with its alpha receptor. Science., 2005, 308, 1477-1480.
24. Thanos, C.D.; DeLano, W.L.; Wells, J.A. Hot-spot mimicry of a cytokine receptor by a small molecule. Proc. Natl. Acad. Sci. U.S.A., 2006, 103, 15422-15427.
25. Kortemme, T.; Baker, D. A simple physical model for binding energy hot spots in protein-protein complexes. Proc. Natl. Acad. Sci. U.S.A., 2002, 99, 14116-14121.
26. Gao, Y.; Wang, R.; Lai, L. Structure-based method for analyzing protein-protein interfaces. J. Mol. Model., 2004, 10, 44-54.
27. Huo, S.; Massova, I.; Kollman, P.A. Computational alanine scanning of the 1:1 human growth hormone-receptor complex. J. Comput. Chem., 2002, 23, 15-27.
28. González-Ruiz, D.; Gohlke, H. Targeting protein-protein interactions with small molecules: challenges and perspectives for computational binding epitope detection and ligand finding. Curr. Med. Chem., 2006, 13, 2607-2625.
29. Tuncbag, N.; Gursoy, A.; Keskin, O. Identification of computational hot spots in protein interfaces: combining solvent accessibility and inter-residue potentials improves the accuracy. Bioinformatics., 2009, 25, 1513-1520.
30. Lise, S.; Archambeau, C.; Pontil, M.; Jones, D. Prediction of hot spot residues at protein-protein interfaces by combining machine learning and energy-based methods. BMC Bioinformatics., 2009, 10, 365.
31. Sonavane, S.; Chakrabarti, P. Cavities and atomic packing in protein structures and interfaces. PLoS Comput. Biol., 2008, 4, e1000188.
32. Laurie, A.T.R.; Jackson, R.M. Methods for the prediction of protein-ligand binding sites for structure-based drug design and virtual ligand screening. Curr. Protein Pept. Sci., 2006, 7, 395-406.
33. Fuller, J.C.; Burgoyne, N.J.; Jackson, R.M. Predicting druggable binding sites at the protein-protein interface. Drug Discov. Today., 2009, 14, 155-161.
34. Eyrisch, S.; Helms, V. Transient pockets on protein surfaces involved in protein-protein interaction. J. Med. Chem., 2007, 50, 3457-3464.
35. Eyrisch, S.; Helms, V. What induces pocket openings on protein surface patches involved in protein-protein interactions? J. Comput. Aided Mol. Des., 2009, 23, 73-86.
36. Brown, S.P.; Hajduk, P.J. Effects of conformational dynamics on predicted protein druggability. ChemMedChem., 2006, 1, 70-72.
37. Lee, G.M.; Craik, C.S. Trapping moving targets with small molecules. Science., 2009, 324, 213-215.
38. Grünberg, R.; Leckner, J.; Nilges, M. Complementarity of structure ensembles in protein-protein binding. Structure., 2004, 12, 2125-2136.
39. Smith, G.R.; Sternberg, M.J. E.; Bates, P.A. The relationship between the flexibility of proteins and their conformational states on forming protein-protein complexes with an application to protein-protein docking. J. Mol. Biol., 2005, 347, 1077-1101.
40. Brady, G.P.; Stouten, P.F. Fast prediction and visualization of protein binding pockets with pass. J. Comput. Aided Mol. Des., 2000, 14, 383-401.
41. Tuncbag, N.; Kar, G.; Keskin, O.; Gursoy, A.; Nussinov, R. A survey of available tools and web servers for analysis of protein-protein interactions and interfaces. Brief. Bioinformatics., 2009, 10, 217-232.
42. Fuentes, G.; Oyarzabal, J.; Rojas, A.M. Databases of protein-protein interactions and their use in drug discovery. Curr. Opin. Drug Discov. Devel., 2009, 12, 358-366.
43. Lehne, B.; Schlitt, T. Protein-protein interaction databases: keeping up with growing interactomes. Hum. Genomics., 2009, 3, 291-297.
44. Finn, R.D.; Marshall, M.; Bateman, A. Ipfam: visualization of protein-protein interactions in pdb at domain and amino acid resolutions. Bioinformatics., 2005, 21, 410-412.
45. Winter, C.; Henschel, A.; Kim, W.K.; Schroeder, M. Scoppi: a structural classification of protein-protein interfaces. Nucleic Acids Res., 2006, 34, D310-314.
46. Jefferson, E.R.; Walsh, T.P.; Roberts, T.J.; Barton, G.J. Snappi-db: a database and api of structures, interfaces and alignments for protein-protein interactions. Nucleic Acids Res., 2007, 35, D580-589.
47. Aloy, P.; Ceulemans, H.; Stark, A.; Russell, R.B. The relationship between sequence and interaction divergence in proteins. J. Mol. Biol., 2003, 332, 989-998.
48. Davis, F.P.; Sali, A. Pibase: a comprehensive database of structurally defined protein interfaces. Bioinformatics., 2005, 21, 1901-1907.
49. Stein, A.; Panjkovich, A.; Aloy, P. 3did update: domain-domain and peptide-mediated interactions of known 3d structure. Nucleic Acids Res., 2009, 37, D300-304.
50. Levy, E.D.; Pereira-Leal, J.B.; Chothia, C.; Teichmann, S.A. 3d complex: a structural classification of protein complexes. PLoS Comput. Biol., 2006, 2, e155.
51. Bordner, A.J.; Gorin, A.A. Comprehensive inventory of protein complexes in the protein data bank from consistent classification of interfaces. BMC Bioinformatics., 2008, 9, 234.
52. Kundrotas, P.J.; Alexov, E. Protcom: searchable database of protein complexes enhanced with domain-domain structures. Nucleic Acids Res., 2007, 35, D575-579.
53. Günther, S.; von Eichborn, J.; May, P.; Preissner, R. Jail: a structure-based interface library for macromolecules. Nucleic Acids Res., 2009, 37, D338-341.
54. Yan, C.; Wu, F.; Jernigan, R.L.; Dobbs, D.; Honavar, V. Characterization of protein-protein interfaces. Protein J., 2008, 27, 59-70.
55. Keskin, O.; Nussinov, R.; Gursoy, A. Prism: protein-protein interaction prediction by structural matching. Methods Mol. Biol., 2008, 484, 505-521.
56. Reynolds, C.; Damerell, D.; Jones, S. Protorp: a protein-protein interaction analysis server. Bioinformatics., 2009, 25, 413-414.
57. Negi, S.S.; Schein, C.H.; Oezguen, N.; Power, T.D.; Braun, W. Interprosurf: a web server for predicting interacting sites on protein surfaces. Bioinformatics., 2007, 23, 3397-3399.
58. Benoit, V.; Mucchielli-Giorgi, M.; Dumont, B.; Durosay, P.; Reymond, N.; Delacroix, H. Ppidd: an extraction and visualisation method of biological protein-protein interfaces. Biochimie., 2008, 90, 640-647.
59. Teyra, J.; Doms, A.; Schroeder, M.; Pisabarro, M.T. Scowlp: a web-based database for detailed characterization and visualization of protein interfaces. BMC Bioinformatics., 2006, 7, 104.
60. Teyra, J.; Pisabarro, M.T. Characterization of interfacial solvent in protein complexes and contribution of wet spots to the interface description. Proteins., 2007, 67, 1087-1095.
61. Thorn, K.S.; Bogan, A.A. Asedb: a database of alanine mutations and their effects on the free energy of binding in protein interactions. Bioinformatics., 2001, 17, 284-285.
62. Fischer, T.B.; Arunachalam, K.V.; Bailey, D.; Mangual, V.; Bakhru, S.; Russo, R.; Huang, D.; Paczkowski, M.; Lalchandani, V.; Ramachandra, C.; Ellison, B.; Galer, S.; Shapley, J.; Fuentes, E.; Tsai, J. The binding interface database (bid): a compilation of amino acid hot spots in protein interfaces. Bioinformatics., 2003, 19, 1453-1454.
63. Guney, E.; Tuncbag, N.; Keskin, O.; Gursoy, A. Hotsprint: database of computational hot spots in protein interfaces. Nucleic Acids Res., 2008, 36, D662-666.
64. Higurashi, M.; Ishida, T.; Kinoshita, K. Pisite: a database of protein interaction sites using multiple binding states in the pdb. Nucleic Acids Res., 2009, 37, D360-364.
65. Gong, S.; Park, C.; Choi, H.; Ko, J.; Jang, I.; Lee, J.; Bolser, D.M.; Oh, D.; Kim, D.; Bhak, J. A protein domain interaction interface database: interpare. BMC Bioinformatics., 2005, 6, 207.
66. Saha, R.P.; Bahadur, R.P.; Pal, A.; Mandal, S.; Chakrabarti, P. Proface: a server for the analysis of the physicochemical features of protein-protein interfaces. BMC Struct. Biol., 2006, 6, 11.
67. Weisel, M.; Proschak, E.; Schneider, G. Pocketpicker: analysis of ligand binding-sites with shape descriptors. Chem. Cent. J., 2007, 1, 7.
68. Laurie, A.T.R.; Jackson, R.M. Q-sitefinder: an energy-based method for the prediction of protein-ligand binding sites. Bioinformatics., 2005, 21, 1908-1916.
69. Huang, B.; Schroeder, M. Ligsitecsc: predicting ligand binding sites using the connolly surface and degree of conservation. BMC Struct. Biol., 2006, 6, 19.
70. Laskowski, R.A. Surfnet: a program for visualizing molecular surfaces, cavities, and intermolecular interactions. Journal of Molecular Graphics., 1995, 13, 323-330.
71. Huang, B. Metapocket: a meta approach to improve protein ligand binding site prediction. OMICS., 2009, 13, 325-330.
72. Betzi, S.; Restouin, A.; Opi, S.; Arold, S.T.; Parrot, I.; Guerlesquin, F.; Morelli, X.; Collette, Y. Protein protein interaction inhibition (2p2i) combining high throughput and virtual screening: application to the hiv-1 nef protein. Proc. Natl. Acad. Sci. U.S.A., 2007, 104, 19256-19261.
73. Betzi, S.; Guerlesquin, F.; Morelli, X. Protein protein interaction inhibition (2p2i):less and less undruggable target? Comb. Chem. & HTS., 2009, 12, 968-983.
74. Betzi, S.; Suhre, K.; Chétrit, B.; Guerlesquin, F.; Morelli, X. Gfscore: a general nonlinear consensus scoring function for high-throughput docking. J. Chem. Inf. Model., 2006, 46, 1704-1712.
75. De Luca, L.; Barreca, M.L.; Ferro, S.; Christ, F.; Iraci, N.; Gitto, R.; Monforte, A.M.; Debyser, Z.; Chimirri, A. Pharmacophore-based discovery of small-molecule inhibitors of protein-protein interactions between hiv-1 integrase and cellular cofactor ledgf/p75. ChemMedChem., 2009, 4, 1311-1316.
76. Caporuscio, F.; Tafi, A.; González, E.; Manetti, F.; Esté, J.A.; Botta, M. A dynamic target-based pharmacophoric model mapping the cd4 binding site on hiv-1 gp120 to identify new inhibitors of gp120-cd4 protein-protein interactions. Bioorg. Med. Chem. Lett., 2009, 19, 6087-6091.
77. Liu, S.; Liu, S.; Fu, Y. Molecular motions of human hiv-1 gp120 envelope glycoproteins. J. Mol. Model., 2008, 14, 857-870.
78. Goodford, P.J. A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. J. Med. Chem., 1985, 28, 849-857.
79. Madani, N.; Perdigoto, A.L.; Srinivasan, K.; Cox, J.M.; Chruma, J.J.; LaLonde, J.; Head, M.; Smith, A.B.; Sodroski, J.G. Localized changes in the gp120 envelope glycoprotein confer resistance to human immunodeficiency virus entry inhibitors bms-806 and #155. J. Virol., 2004, 78, 3742-3752.
80. Oltersdorf, T.; Elmore, S.W.; Shoemaker, A.R.; et al. An inhibitor of bcl-2 family proteins induces regression of solid tumours. Nature., 2005, 435, 677-681.
81. Becattini, B.; Kitada, S.; Leone, M.; Monosov, E.; Chandler, S.; Zhai, D.; Kipps, T.J.; Reed, J.C.; Pellecchia, M. Rational design and real time, in-cell detection of the proapoptotic activity of a novel compound targeting bcl-x(l). Chem. Biol., 2004, 11, 389-395.
82. Kitada, S.; Leone, M.; Sareth, S.; Zhai, D.; Reed, J.C.; Pellecchia, M. Discovery, characterization, and structure-activity relationships studies of proapoptotic polyphenols targeting b-cell lymphocyte/leukemia-2 proteins. J. Med. Chem., 2003, 46, 4259-4264.
83. Wang, J.L.; Liu, D.; Zhang, Z.J.; Shan, S.; Han, X.; Srinivasula, S.M.; Croce, C.M.; Alnemri, E.S.; Huang, Z. Structurebased discovery of an organic compound that binds bcl-2 protein and induces apoptosis of tumor cells. Proc. Natl. Acad. Sci. U.S.A., 2000, 97, 7124-7129.
84. Shuker, S.B.; Hajduk, P.J.; Meadows, R.P.; Fesik, S.W. Discovering high-affinity ligands for proteins: sar by nmr. Science., 1996, 274, 1531-1534.
85. Rubinstein, M.; Niv, M.Y. Peptidic modulators of protein-protein interactions: progress and challenges in computational design. Biopolymers., 2009, 91, 505-513.
86. Laudet, B.; Barette, C.; Dulery, V.; Renaudet, O.; Dumy, P.; Metz, A.; Prudent, R.; Deshiere, A.; Dideberg, O.; Filhol, O.; Cochet, C. Structure-based design of small peptide inhibitors of protein kinase ck2 subunit interaction. Biochem. J., 2007, 408, 363-373.
87. Vagner, J.; Qu, H.; Hruby, V.J. Peptidomimetics, a synthetic tool of drug discovery. Curr. Opin. Chem. Biol., 2008, 12, 292-296.
88. Rodriguez, J.M.; Nevola, L.; Ross, N.T.; Lee, G.; Hamilton, A.D. Synthetic inhibitors of extended helix-protein interactions based on a biphenyl 4,4'-dicarboxamide scaffold. Chembiochem., 2009, 10, 829-833.
89. Jacoby, E. Biphenyls as potential mimetics of protein alpha-helix. Bioorg. Med. Chem. Lett., 2002, 12, 891-893.
90. Orner, B.P.; Ernst, J.T.; Hamilton, A.D. Toward proteomimetics: terphenyl derivatives as structural and functional mimics of extended regions of an alpha-helix. J. Am. Chem. Soc., 2001, 123, 5382-5383.
91. Yin, H.; Lee, G.; Sedey, K.A.; Kutzki, O.; Park, H.S.; Orner, B.P.; Ernst, J.T.; Wang, H.; Sebti, S.M.; Hamilton, A.D. Terphenyl-based bak bh3 alpha-helical proteomimetics as low-molecular-weight antagonists of bcl-xl. J. Am. Chem. Soc., 2005, 127, 10191-10196.
92. Yin, H.; Lee, G.; Park, H.S.; Payne, G.A.; Rodriguez, J.M.; Sebti, S.M.; Hamilton, A.D. Terphenyl-based helical mimetics that disrupt the p53/hdm2 interaction. Angew. Chem. Int. Ed. Engl., 2005, 44, 2704-2707.
93. Yin, H.; Lee, G.; Park, H.S.; Payne, G.A.; Rodriguez, J.M.; Sebti, S.M.; Hamilton, A.D. Terphenyl-based helical mimetics that disrupt the p53/hdm2 interaction. Angew. Chem. Int. Ed. Engl., 2005, 44, 2704-2707.
94. Shangary, S.; Wang, S. Small-molecule inhibitors of the mdm2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy. Annu. Rev. Pharmacol. Toxicol., 2009, 49, 223-241.
95. Saraogi, I.; Hamilton, A.D. Alpha-helix mimetics as inhibitors of protein-protein interactions. Biochem. Soc. Trans., 2008, 36, 1414-1417.
96. Gavathiotis, E.; Suzuki, M.; Davis, M.L.; Pitter, K.; Bird, G.H.; Katz, S.G.; Tu, H.; Kim, H.; Cheng, E.H.; Tjandra, N.; Walensky, L.D. Bax activation is initiated at a novel interaction site. Nature., 2008, 455, 1076-1081.
97. Walensky, L.D.; Kung, A.L.; Escher, I.; Malia, T.J.; Barbuto, S.; Wright, R.D.; Wagner, G.; Verdine, G.L.; Korsmeyer, S.J. Activation of apoptosis in vivo by a hydrocarbon-stapled bh3 helix. Science., 2004, 305, 1466-1470.
98. Walensky, L.D.; Pitter, K.; Morash, J.; Oh, K.J.; Barbuto, S.; Fisher, J.; Smith, E.; Verdine, G.L.; Korsmeyer, S.J. A stapled bid bh3 helix directly binds and activates bax. Mol. Cell., 2006, 24, 199-210.
99. Goede, A.; Michalsky, E.; Schmidt, U.; Preissner, R. Supermimic--fitting peptide mimetics into protein structures. BMC Bioinformatics., 2006, 7, 11.
100. Eckert, H.; Bajorath, J. Exploring peptide-likeness of active molecules using 2d fingerprint methods. J. Chem. Inf. Model., 2007, 47, 1366-1378.
101. Parthasarathi, L.; Casey, F.; Stein, A.; Aloy, P.; Shields, D.C. Approved drug mimics of short peptide ligands from protein interaction motifs. J. Chem. Inf. Model., 2008, 48, 1943-1948.
102. Bourgeas, R.; Basse, M.; Morelli, X.; Roche, P. Atomic analysis of protein-protein interfaces with known inhibitors: the 2p2i database. PLoS ONE. 2010, 5, e9598.
103. Alsafadi, S.; Tourpin, S.; André, F.; Vassal, G.; Ahomadegbe, J. P53 family: at the crossroads in cancer therapy. Curr. Med. Chem., 2009, 16, 4328-4344.
104. Kussie, P.H.; Gorina, S.; Marechal, V.; Elenbaas, B.; Moreau, J.; Levine, A.J.; Pavletich, N.P. Structure of the mdm2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science., 1996, 274, 948-953.
105. Hasegawa, H.; Yamada, Y.; Iha, H.; Tsukasaki, K.; Nagai, K.; Atogami, S.; Sugahara, K.; Tsuruda, K.; Ishizaki, A.; Kamihira, S. Activation of p53 by nutlin-3a, an antagonist of mdm2, induces apoptosis and cellular senescence in adult tcell leukemia cells. Leukemia., 2009, 23, 2090-2101.
106. Lee, Y.; Lim, J.; Chun, Y.; Moon, H.; Lee, M.K.; Huang, L.E.; Park, J. Nutlin-3, an hdm2 antagonist, inhibits tumor adaptation to hypoxia by stimulating the fih-mediated inactivation of hif-1alpha. Carcinogenesis., 2009, 30, 1768-1775.
107. Morselli, E.; Galluzzi, L.; Kepp, O.; Kroemer, G. Nutlin kills cancer cells via mitochondrial p53. Cell Cycle., 2009, 8, 1647-1648.
108. Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Qiu, S.; Ding, Y.; Gao, W.; Stuckey, J.; Krajewski, K.; Roller, P.P.; Tomita, Y.; Parrish, D.A.; Deschamps, J.R.; Wang, S. Structure-based design of potent non-peptide mdm2 inhibitors. J. Am. Chem. Soc., 2005, 127, 10130-10131.
109. Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Wang, G.; Qiu, S.; Shangary, S.; Gao, W.; Qin, D.; Stuckey, J.; Krajewski, K.; Roller, P.P.; Wang, S. Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the mdm2-p53 interaction. J. Med. Chem., 2006, 49, 3432-3435.
110. Grasberger, B.L.; Lu, T.; Schubert, C.; Parks, D.J.; Carver, T.E.; Koblish, H.K.; Cummings, M.D.; LaFrance, L.V.; Milkiewicz, K.L.; Calvo, R.R.; Maguire, D.; Lattanze, J.; Franks, C.F.; Zhao, S.; Ramachandren, K.; Bylebyl, G.R.; Zhang, M.; Manthey, C.L.; Petrella, E.C.; Pantoliano, M.W.; Deckman, I.C.; Spurlino, J.C.; Maroney, A.C.; Tomczuk, B.E.; Molloy, C.J.; Bone, R.F. Discovery and cocrystal structure of benzodiazepinedione hdm2 antagonists that activate p53 in cells. J. Med. Chem., 2005, 48, 909-912.
111. Parks, D.J.; Lafrance, L.V.; Calvo, R.R.; Milkiewicz, K.L.; Gupta, V.; Lattanze, J.; Ramachandren, K.; Carver, T.E.; Petrella, E.C.; Cummings, M.D.; Maguire, D.; Grasberger, B.L.; Lu, T. 1,4-benzodiazepine-2,5-diones as small molecule antagonists of the hdm2-p53 interaction: discovery and sar. Bioorg. Med. Chem. Lett., 2005, 15, 765-770.
112. Lu, Y.; Nikolovska-Coleska, Z.; Fang, X.; Gao, W.; Shangary, S.; Qiu, S.; Qin, D.; Wang, S. Discovery of a nanomolar inhibitor of the human murine double minute 2 (mdm2)-p53 interaction through an integrated, virtual database screening strategy. J. Med. Chem., 2006, 49, 3759-3762.
113. Rothweiler, U.; Czarna, A.; Krajewski, M.; Ciombor, J.; Kalinski, C.; Khazak, V.; Ross, G.; Skobeleva, N.; Weber, L.; Holak, T.A. Isoquinolin-1-one inhibitors of the mdm2-p53 interaction. ChemMedChem., 2008, 3, 1118-1128.
114. Stoll, R.; Renner, C.; Hansen, S.; Palme, S.; Klein, C.; Belling, A.; Zeslawski, W.; Kamionka, M.; Rehm, T.; Mühlhahn, P.; Schumacher, R.; Hesse, F.; Kaluza, B.; Voelter, W.; Engh, R.A.; Holak, T.A. Chalcone derivatives antagonize interactions between the human oncoprotein mdm2 and p53. Biochemistry., 2001, 40, 336-344.
115. Galatin, P.S.; Abraham, D.J. A nonpeptidic sulfonamide inhibits the p53-mdm2 interaction and activates p53-dependent transcription in mdm2-overexpressing cells. J. Med. Chem., 2004, 47, 4163-4165.
116. Allen, J.G.; Bourbeau, M.P.; Wohlhieter, G.E.; Bartberger, M.D.; Michelsen, K.; Hungate, R.; Gadwood, R.C.; Gaston, R.D.; Evans, B.; Mann, L.W.; Matison, M. E.; Schneider, S.; Huang, X.; Yu, D.; Andrews, P.S.; Reichelt, A.; Long, A.M.; Yakowec, P.; Yang, E.Y.; Lee, T.A.; Oliner, J.D. Discovery and optimization of chromenotriazolopyrimidines as potent inhibitors of the mouse double minute 2-tumor protein 53 protein-protein interaction. J. Med. Chem., 2009, 52, 7044-7053.
117. Vassilev, L.T.; Vu, B.T.; Graves, B.; Carvajal, D.; Podlaski, F.; Filipovic, Z.; Kong, N.; Kammlott, U.; Lukacs, C.; Klein, C.; Fotouhi, N.; Liu, E.A. In vivo activation of the p53 pathway by small-molecule antagonists of mdm2. Science., 2004, 303, 844-848.
118. Bowman, A.L.; Nikolovska-Coleska, Z.; Zhong, H.; Wang, S.; Carlson, H.A. Small molecule inhibitors of the mdm2-p53 interaction discovered by ensemble-based receptor models. J. Am. Chem. Soc., 2007, 129, 12809-12814.
119. Fry, D.C.; Emerson, S.D.; Palme, S.; Vu, B. T.; Liu, C.; Podlaski, F. Nmr structure of a complex between mdm2 and a small molecule inhibitor. J. Biomol. NMR., 2004, 30, 163-173.
120. Hyde, J.; Braisted, A.C.; Randal, M.; Arkin, M.R. Discovery and characterization of cooperative ligand binding in the adaptive region of interleukin-2. Biochemistry., 2003, 42, 6475-6483.
121. Braisted, A.C.; Oslob, J.D.; Delano, W.L.; Hyde, J.; McDowell, R.S.; Waal, N.; Yu, C.; Arkin, M.R.; Raimundo, B.C. Discovery of a potent small molecule il-2 inhibitor through fragment assembly. J. Am. Chem. Soc., 2003, 125, 3714-3715.
122. Waal, N.D.; Yang, W.; Oslob, J.D.; Arkin, M.R.; Hyde, J.; Lu, W.; McDowell, R.S.; Yu, C.H.; Raimundo, B.C. Identification of nonpeptidic small-molecule inhibitors of interleukin-2. Bioorg. Med. Chem. Lett., 2005, 15, 983-987.
123. Thanos, C.D.; Randal, M.; Wells, J.A. Potent small-molecule binding to a dynamic hot spot on il-2. J. Am. Chem. Soc., 2003, 125, 15280-15281.
124. Raimundo, B.C.; Oslob, J.D.; Braisted, A.C.; Hyde, J.; McDowell, R.S.; Randal, M.; Waal, N.D.; Wilkinson, J.; Yu, C.H.; Arkin, M.R. Integrating fragment assembly and biophysical methods in the chemical advancement of small-molecule antagonists of il-2: an approach for inhibiting protein-protein interactions. J. Med. Chem., 2004, 47, 3111-3130.
125. Petros, A.M.; Olejniczak, E.T.; Fesik, S.W. Structural biology of the bcl-2 family of proteins. Biochim. Biophys. Acta., 2004, 1644, 83-94.
126. Kang, M.H.; Reynolds, C.P. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin. Cancer Res., 2009, 15, 1126-1132.
127. Azmi, A.S.; Mohammad, R.M. Non-peptidic small molecule inhibitors against bcl-2 for cancer therapy. J. Cell. Physiol., 2009, 218, 13-21.
128. Bruncko, M.; Oost, T.K.; Belli, B.A.; Ding, H.; Joseph, M.K.; Kunzer, A.; Martineau, D.; McClellan, W.J.; Mitten, M.; Ng, S.; Nimmer, P.M.; Oltersdorf, T.; Park, C.; Petros, A.M.; Shoemaker, A.R.; Song, X.; Wang, X.; Wendt, M.D.; Zhang, H.; Fesik, S.W.; Rosenberg, S.H.; Elmore, S.W. Studies leading to potent, dual inhibitors of bcl-2 and bcl-xl. J. Med. Chem., 2007, 50, 641-662.
129. Stauffer, S.R. Small molecule inhibition of the bcl-x(l)-bh3 protein-protein interaction: proof-of-concept of an in vivo chemopotentiator abt-737. Curr. Top. Med. Chem., 2007, 7, 961-965.
130. Lee, E.F.; Czabotar, P.E.; Smith, B.J.; Deshayes, K.; Zobel, K.; Colman, P.M.; Fairlie, W.D. Crystal structure of abt-737 complexed with bcl-xl: implications for selectivity of antagonists of the bcl-2 family. Cell Death Differ., 2007, 14, 1711-1713.
131. Verhaegen, M.; Bauer, J.A.; Martín de la Vega, C.; Wang, G.; Wolter, K.G.; Brenner, J.C.; Nikolovska-Coleska, Z.; Bengtson, A.; Nair, R.; Elder, J.T.; Van Brocklin, M.; Carey, T.E.; Bradford, C.R.; Wang, S.; Soengas, M.S. A novel bh3 mimetic reveals a mitogen-activated protein kinase-dependent mechanism of melanoma cell death controlled by p53 and reactive oxygen species. Cancer Res., 2006, 66, 11348-11359.
132. Wang, Z.; Azmi, A.S.; Ahmad, A.; Banerjee, S.; Wang, S.; Sarkar, F.H.; Mohammad, R.M. Tw-37, a small-molecule inhibitor of bcl-2, inhibits cell growth and induces apoptosis in pancreatic cancer: involvement of notch-1 signaling pathway. Cancer Res., 2009, 69, 2757-2765.
133. Rezazadeh, A.; Laber, D.A.; Ghim, S.; Jenson, A.B.; Kloecker, G. The role of human papilloma virus in lung cancer: a review of the evidence. Am. J. Med. Sci., 2009, 338, 64-67.
134. Kasukawa, H.; Howley, P.M.; Benson, J.D. A fifteen-amino-acid peptide inhibits human papillomavirus e1-e2 interaction and human papillomavirus dna replication in vitro. J. Virol., 1998, 72, 8166-8173.
135. Yoakim, C.; Ogilvie, W.W.; Goudreau, N.; Naud, J.; Haché, B.; O'Meara, J.A.; Cordingley, M.G.; Archambault, J.; White, P.W. Discovery of the first series of inhibitors of human papillomavirus type 11: inhibition of the assembly of the e1-e2-origin dna complex. Bioorg. Med. Chem. Lett., 2003, 13, 2539-2541.
136. White, P.W.; Titolo, S.; Brault, K.; Thauvette, L.; Pelletier, A.; Welchner, E.; Bourgon, L.; Doyon, L.; Ogilvie, W.W.; Yoakim, C.; Cordingley, M.G.; Archambault, J. Inhibition of human papillomavirus dna replication by small molecule antagonists of the e1-e2 protein interaction. J. Biol. Chem., 2003, 278, 26765-26772.
137. Goudreau, N.; Cameron, D.R.; Déziel, R.; Haché, B.; Jakalian, A.; Malenfant, E.; Naud, J.; Ogilvie, W.W.; O'meara, J.; White, P.W.; Yoakim, C. Optimization and determination of the absolute configuration of a series of potent inhibitors of human papillomavirus type-11 e1-e2 protein-protein interaction: a combined medicinal chemistry, nmr and computational chemistry approach. Bioorg. Med. Chem., 2007, 15, 2690-2700.
138. Wang, Y.; Coulombe, R.; Cameron, D.R.; Thauvette, L.; Massariol, M.; Amon, L.M.; Fink, D.; Titolo, S.; Welchner, E.; Yoakim, C.; Archambault, J.; White, P.W. Crystal structure of the e2 transactivation domain of human papillomavirus type 11 bound to a protein interaction inhibitor. J. Biol. Chem., 2004, 279, 6976-6985.
139. Abbate, E.A.; Berger, J.M.; Botchan, M.R. The x-ray structure of the papillomavirus helicase in complex with its molecular matchmaker e2. Genes Dev., 2004, 18, 1981-1996.
140. He, M.M.; Smith, A.S.; Oslob, J.D.; Flanagan, W.M.; Braisted, A.C.; Whitty, A.; Cancilla, M.T.; Wang, J.; Lugovskoy, A.A.; Yoburn, J.C.; Fung, A.D.; Farrington, G.; Eldredge, J.K.; Day, E.S.; Cruz, L.A.; Cachero, T.G.; Miller, S.K.; Friedman, J.E.; Choong, I.C.; Cunningham, B.C. Small-molecule inhibition of tnf-alpha. Science., 2005, 310, 1022-1025.
141. Chen, D.J.; Huerta, S. Smac mimetics as new cancer therapeutics. Anticancer. Drugs., 2009, 20, 646-658.
142. Wu, G.; Chai, J.; Suber, T.L.; Wu, J.W.; Du, C.; Wang, X.; Shi, Y. Structural basis of iap recognition by smac/diablo. Nature., 2000, 408, 1008-1012.
143. Nikolovska-Coleska, Z.; Xu, L.; Hu, Z.; Tomita, Y.; Li, P.; Roller, P.P.; Wang, R.; Fang, X.; Guo, R.; Zhang, M.; Lippman, M.E.; Yang, D.; Wang, S. Discovery of embelin as a cell-permeable, small-molecular weight inhibitor of xiap through structure-based computational screening of a traditional herbal medicine three-dimensional structure database. J. Med. Chem., 2004, 47, 2430-2440.
144. Chen, J.; Nikolovska-Coleska, Z.; Wang, G.; Qiu, S.; Wang, S. Design, synthesis, and characterization of new embelin derivatives as potent inhibitors of x-linked inhibitor of apoptosis protein. Bioorg. Med. Chem. Lett., 2006, 16, 5805-5808.
145. Sun, H.; Stuckey, J.A.; Nikolovska-Coleska, Z.; Qin, D.; Meagher, J.L.; Qiu, S.; Lu, J.; Yang, C.; Saito, N.G.; Wang, S. Structure-based design, synthesis, evaluation, and crystallographic studies of conformationally constrained smac mimetics as inhibitors of the x-linked inhibitor of apoptosis protein (xiap). J. Med. Chem., 2008, 51, 7169-7180.
146. Mastrangelo, E.; Cossu, F.; Milani, M.; Sorrentino, G.; Lecis, D.; Delia, D.; Manzoni, L.; Drago, C.; Seneci, P.; Scolastico, C.; Rizzo, V.; Bolognesi, M. Targeting the x-linked inhibitor of apoptosis protein through 4-substituted azabicyclo[5.3.0]alkane smac mimetics. structure, activity, and recognition principles. J. Mol. Biol., 2008, 384, 673-689.
147. Cossu, F.; Mastrangelo, E.; Milani, M.; Sorrentino, G.; Lecis, D.; Delia, D.; Manzoni, L.; Seneci, P.; Scolastico, C.; Bolognesi, M. Designing smac-mimetics as antagonists of xiap, ciap1, and ciap2. Biochem. Biophys. Res. Commun., 2009, 378, 162-167.
148. Seneci, P.; Bianchi, A.; Battaglia, C.; Belvisi, L.; Bolognesi, M.; Caprini, A.; Cossu, F.; Franco, E.D.; Matteo, M.D.; Delia, D.; Drago, C.; Khaled, A.; Lecis, D.; Manzoni, L.; Marizzoni, M.; Mastrangelo, E.; Milani, M.; Motto, I.; Moroni, E.; Potenza, D.; Rizzo, V.; Servida, F.; Turlizzi, E.; Varrone, M.; Vasile, F.; Scolastico, C. Rational design, synthesis and characterization of potent, non-peptidic smac mimics/xiap inhibitors as proapoptotic agents for cancer therapy. Bioorganic & Medicinal Chemistry., 2009, 17, 5834-5856.
149. Wang, N.X.; Lee, H.; Zheng, J.J. Therapeutic use of pdz protein-protein interaction antagonism. Drug News Perspect., 2008, 21, 137-141.
150. Fujii, N.; Haresco, J.J.; Novak, K.A.P.; Gage, R.M.; Pedemonte, N.; Stokoe, D.; Kuntz, I.D.; Guy, R.K. Rational design of a nonpeptide general chemical scaffold for reversible inhibition of pdz domain interactions. Bioorg. Med. Chem. Lett., 2007, 17, 549-552.
151. Grandy, D.; Shan, J.; Zhang, X.; Rao, S.; Akunuru, S.; Li, H.; Zhang, Y.; Alpatov, I.; Zhang, X.A.; Lang, R.A.; Shi, D.; Zheng, J.J. Discovery and characterization of a small molecule inhibitor of the pdz domain of dishevelled. J. Biol. Chem., 2009, 284, 16256-16263.
152. Shan, J.; Zheng, J.J. Optimizing dvl pdz domain inhibitor by exploring chemical space. J. Comput. Aided Mol. Des., 2009, 23, 37-47.
153. Uvebrant, K.; da Graça Thrige, D.; Rosén, A.; Akesson, M.; Berg, H.; Walse, B.; Björk, P. Discovery of selective smallmolecule cd80 inhibitors. J. Biomol. Screen., 2007, 12, 464-472.
154. Yabu, J.M.; Vincenti, F. Novel immunosuppression: small molecules and biologics. Semin. Nephrol., 2007, 27, 479-486.
155. Kadow, J.; Wang, H.H.; Lin, P. Small-molecule hiv-1 gp120 inhibitors to prevent hiv-1 entry: an emerging opportunity for drug development. Curr. Opin. Investig. Drugs., 2006, 7, 721-726.
156. Tilton, J.C.; Doms, R.W. Entry inhibitors in the treatment of hiv-1 infection. Antiviral Res., 2010, 85, 91-100.
157. Tran, T.; Adam, F.M.; Calo, F.; Fenwick, D.R.; Fok-Seang, J.; Gardner, I.; Hay, D.A.; Perros, M.; Rawal, J.; Middleton, D.S.; Parkinson, T.; Pickford, C.; Platts, M.; Randall, A.; Stephenson, P.T.; Vuong, H.; Williams, D.H. Design and optimisation of potent gp120-cd4 inhibitors. Bioorg. Med. Chem. Lett., 2009, 19, 5250-5255.
158. Williams, D.H.; Adam, F.; Fenwick, D.R.; Fok-Seang, J.; Gardner, I.; Hay, D.; Jaiessh, R.; Middleton, D.S.; Mowbray, C.E.; Parkinson, T.; Perros, M.; Pickford, C.; Platts, M.; Randall, A.; Siddle, D.; Stephenson, P.T.; Tran, T.; Vuong, H. Discovery of a small molecule inhibitor through interference with the gp120-cd4 interaction. Bioorg. Med. Chem. Lett., 2009, 19, 5246-5249.
159. Lin, P.; Blair, W.; Wang, T.; Spicer, T.; Guo, Q.; Zhou, N.; Gong, Y.; Wang, H.H.; Rose, R.; Yamanaka, G.; Robinson, B.; Li, C.; Fridell, R.; Deminie, C.; Demers, G.; Yang, Z.; Zadjura, L.; Meanwell, N.; Colonno, R. A small molecule hiv-1 inhibitor that targets the hiv-1 envelope and inhibits cd4 receptor binding. Proc. Natl. Acad. Sci. U.S.A., 2003, 100, 11013-11018.
160. Engelman, A. Mechanistic and pharmacological analyses of hiv-1 integration. Methods., 2009, 47, 225-228.
161. Marchand, C.; Maddali, K.; Métifiot, M.; Pommier, Y. Hiv-1 in inhibitors: 2010 update and perspectives. Curr. Top. Med. Chem., 2009, 9, 1016-1037.
162. Du, L.; Zhao, Y.; Chen, J.; Yang, L.; Zheng, Y.; Tang, Y.; Shen, X.; Jiang, H. D77, one benzoic acid derivative, functions as a novel anti-hiv-1 inhibitor targeting the interaction between integrase and cellular ledgf/p75. Biochem. Biophys. Res. Commun., 2008, 375, 139-144.
163. Tsao, D.H.H.; Sutherland, A.G.; Jennings, L.D.; Li, Y.; Rush, T.S.; Alvarez, J.C.; Ding, W.; Dushin, E.G.; Dushin, R.G.; Haney, S.A.; Kenny, C.H.; Malakian, A.K.; Nilakantan, R.; Mosyak, L. Discovery of novel inhibitors of the zipa/ftsz complex by nmr fragment screening coupled with structure-based design. Bioorg. Med. Chem., 2006, 14, 7953-7961.
164. Jennings, L.D.; Foreman, K.W.; Rush, T.S.; Tsao, D.H.H.; Mosyak, L.; Kincaid, S.L.; Sukhdeo, M.N.; Sutherland, A.G.; Ding, W.; Kenny, C.H.; Sabus, C.L.; Liu, H.; Dushin, E.G.; Moghazeh, S.L.; Labthavikul, P.; Petersen, P.J.; Tuckman, M.; Haney, S.A.; Ruzin, A.V. Combinatorial synthesis of substituted 3-(2-indolyl)piperidines and 2-phenyl indoles as inhibitors of zipa-ftsz interaction. Bioorg. Med. Chem., 2004, 12, 5115-5131.
165. Jennings, L.D.; Foreman, K.W.; Rush, T.S.; Tsao, D.H.H.; Mosyak, L.; Li, Y.; Sukhdeo, M.N.; Ding, W.; Dushin, E.G.; Kenny, C.H.; Moghazeh, S.L.; Petersen, P.J.; Ruzin, A.V.; Tuckman, M.; Sutherland, A.G. Design and synthesis of indolo[2,3-a]quinolizin-7-one inhibitors of the zipa-ftsz interaction. Bioorg. Med. Chem. Lett., 2004, 14, 1427-1431.
166. Rush, T.S.; Grant, J.A.; Mosyak, L.; Nicholls, A. A shape-based 3-d scaffold hopping method and its application to a bacterial protein-protein interaction. J. Med. Chem., 2005, 48, 1489-1495.
167. Novak, W.; Wang, H.; Krilov, G. Role of protein flexibility in the design of bcl-x(l) targeting agents: insight from molecular dynamics. J. Comput. Aided Mol. Des., 2009, 23, 49-61.
168. Tama, F.; Brooks, C.L. Symmetry, form, and shape: guiding principles for robustness in macromolecular machines. Annu. Rev. Biophys. Biomol. Struct., 2006, 35, 115-133.
169. Higueruelo, A.P.; Schreyer, A.; Bickerton, G.R.J.; Pitt, W.R.; Groom, C.R.; Blundell, T.L. Atomic interactions and profile of small molecules disrupting protein-protein interfaces: the timbal database. Chem. Biol. Drug Des., 2009, 74, 457-467.
170. Reynès, C.; Host, H.; Camproux, A.; Laconde, G.; Leroux, F.; Mazars, A.; Deprez, B.; Fahraeus, R.; Villoutreix, B.O.; Sperandio, O. Designing focused chemical libraries enriched in protein-protein interaction inhibitors using machinelearning methods. PLoS Comput. Biol., 2010, 6, e1000695.
171. Sperandio, O.; Reynès, C.H.; Camproux, A.; Villoutreix, B.O. Rationalizing the chemical space of protein-protein interaction inhibitors. Drug Discov. Today., 2010, 15, 220-229.
172. Oost, T.K.; Sun, C.; Armstrong, R.C.; Al-Assaad, A.; Betz, S.F.; Deckwerth, T. L.; Ding, H.; Elmore, S.W.; Meadows, R.P.; Olejniczak, E.T.; Oleksijew, A.; Oltersdorf, T.; Rosenberg, S.H.; Shoemaker, A.R.; Tomaselli, K.J.; Zou, H.; Fesik, S. W. Discovery of potent antagonists of the antiapoptotic protein xiap for the treatment of cancer. J. Med. Chem., 2004, 47, 4417-4426.
173. Wist, A.D.; Gu, L.; Riedl, S.J.; Shi, Y.; McLendon, G.L. Structure-activity based study of the smac-binding pocket within the bir3 domain of xiap. Bioorg. Med. Chem., 2007, 15, 2935-2943.
174. Tsuge, H.; Nishimura, T.; Tada, Y.; Asao, T.; Turk, D.; Turk, V.; Katunuma, N. Inhibition mechanism of cathepsin lspecific inhibitors based on the crystal structure of papain-clik148 complex. Biochem. Biophys. Res. Commun., 1999, 266, 411-416.
175. Arkin, M.R.; Randal, M.; DeLano, W.L.; Hyde, J.; Luong, T.N.; Oslob, J.D.; Raphael, D.R.; Taylor, L.; Wang, J.; McDowell, R.S.; Wells, J.A.; Braisted, A.C. Binding of small molecules to an adaptive protein-protein interface. Proc. Natl. Acad. Sci. U.S.A., 2003, 100, 1603-1608.
176. Lovejoy, B.; Welch, A.R.; Carr, S.; Luong, C.; Broka, C.; Hendricks, R.T.; Campbell, J.A.; Walker, K.A.; Martin, R.; Van Wart, H.; Browner, M.F. Crystal structures of mmp-1 and -13 reveal the structural basis for selectivity of collagenase inhibitors. Nat. Struct. Biol., 1999, 6, 217-221.
177. Finzel, B.C.; Baldwin, E.T.; Bryant, G.L.; Hess, G.F.; Wilks, J.W.; Trepod, C.M.; Mott, J.E.; Marshall, V.P.; Petzold, G.L.; Poorman, R.A.; O'Sullivan, T.J.; Schostarez, H.J.; Mitchell, M.A. Structural characterizations of nonpeptidic thiadiazole inhibitors of matrix metalloproteinases reveal the basis for stromelysin selectivity. Protein Sci., 1998, 7, 2118-2126.
178. Eschenburg, S.; Genov, N.; Peters, K.; Fittkau, S.; Stoeva, S.; Wilson, K.S.; Betzel, C. Crystal structure of subtilisin dy, a random mutant of subtilisin carlsberg. Eur. J. Biochem., 1998, 257, 309-318.
179. Dubowchik, G.M.; Vrudhula, V.M.; Dasgupta, B.; Ditta, J.; Chen, T.; Sheriff, S.; Sipman, K.; Witmer, M.; Tredup, J.; Vyas, D.M.; Verdoorn, T.A.; Bollini, S.; Vinitsky, A. 2-aryl-2,2-difluoroacetamide fkbp12 ligands: synthesis and x-ray structural studies. Org. Lett., 2001, 3, 3987-3990.
180. Lévesque, S.; St-Denis, Y.; Bachand, B.; Préville, P.; Leblond, L.; Winocour, P.D.; Edmunds, J.J.; Rubin, J.R.; Siddiqui, M.A. Novel bicyclic lactam inhibitors of thrombin: potency and selectivity optimization through p1 residues. Bioorg. Med. Chem. Lett., 2001, 11, 3161-3164.
181. Lee, S.L.; Alexander, R.S.; Smallwood, A.; Trievel, R.; Mersinger, L.; Weber, P.C.; Kettner, C. New inhibitors of thrombin and other trypsin-like proteases: hydrogen bonding of an aromatic cyano group with a backbone amide of the p1 binding site replaces binding of a basic side chain. Biochemistry., 1997, 36, 13180-13186.