Fragment-based optimization of small molecule CXCL12 inhibitors for antagonizing the CXCL12/CXCR4 interaction

Current Topics in Medicinal Chemistry

Volumn 12, Issue 24, 2012, Pages 2727-2740

  Ziarek, Joshua J ^b   Liu, Yan ^a   Smith, Emmanuel ^c   Zhang, Guolin ^d   Peterson, Francis C ^b   Chen, Jun ^d   Yu, Yongping ^d   Chen, Yu ^c   Volkman, Brian F ^b   Li, Rongshi ^a,c  

^a H LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE   (United States)

^b MEDICAL COLLEGE OF WISCONSIN   (United States)

^c UNIVERSITY OF SOUTH FLORIDA   (United States)

^d ZHEJIANG UNIVERSITY   (China)

Author keywords

Chemokines; CXCL12 CXCR4 inhibitors; Fragment based and structureguided drug design; Metastasis; Protein protein interaction

Indexed keywords

CHEMOKINE RECEPTOR CXCR4 ANTAGONIST; CHEMOKINE RECEPTOR CXCR7; STROMAL CELL DERIVED FACTOR 1; TETRAZOLE DERIVATIVE; ANTINEOPLASTIC AGENT; CHEMOKINE RECEPTOR CXCR4; CXCL12 PROTEIN, HUMAN; CXCR4 PROTEIN, HUMAN; DRUG DERIVATIVE; TUMOR PROTEIN; TYROSINE; TYROSINE O-SULFATE; TYROSINE SULFATE;

ARTICLE; CELL MIGRATION; DRUG DESIGN; HUMAN; METASTASIS; MOLECULAR DOCKING; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PROCESS OPTIMIZATION; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; QUANTITATIVE STRUCTURE ACTIVITY RELATION; VIRUS REPLICATION; X RAY CRYSTALLOGRAPHY; BINDING SITE; CHEMISTRY; DRUG ANTAGONISM; MOLECULAR LIBRARY; PROTEIN BINDING;

ANTINEOPLASTIC AGENTS; BINDING SITES; CHEMOKINE CXCL12; DRUG DESIGN; HUMANS; MOLECULAR DOCKING SIMULATION; NEOPLASM PROTEINS; PROTEIN BINDING; RECEPTORS, CXCR4; SMALL MOLECULE LIBRARIES; TETRAZOLES; TYROSINE;

EID: 84883719150     PISSN: 15680266     EISSN: 18734294     Source Type: Journal    
DOI: 10.2174/1568026611212240003     Document Type: Article

References (152)

1. Zou, Y. R.; Kottmann, A. H.; Kuroda, M.; Taniuchi, I.; Littman, D. R. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature, 1998, 393, 595-599.
2. Wang, J. M.; Deng, X.; Gong, W.; Su, S. Chemokines and their role in tumor growth and metastasis. J. Immunol. Methods, 1998, 220, 1-17.
3. Strieter, R. M. Chemokines: not just leukocyte chemoattractants in the promotion of cancer. Nat. Immunol., 2001, 2, 285-286.
4. Rossi, D.; Zlotnik, A. The biology of chemokines and their receptors. Annu. Rev. Immunol., 2000, 18, 217-242.
5. Baggiolini, M. Chemokines in pathology and medicine. J. Intern. Med., 2001, 250, 91-104.
6. Gerard, C.; Rollins, B. J. Chemokines and disease. Nat. Immunol., 2001, 2, 108-115.
7. Proudfoot, A. E. Chemokine receptors: multifaceted therapeutic targets. Nat. Rev. Immunol., 2002, 2, 106-115.
8. Muller, A.; Homey, B.; Soto, H.; Ge, N.; Catron, D.; Buchanan, M. E.; McClanahan, T.; Murphy, E.; Yuan, W.; Wagner, S. N.; Barrera, J. L.; Mohar, A.; Verastegui, E.; Zlotnik, A.: Involvement of chemokine receptors in breast cancer metastasis. Nature, 2001, 410, 50-56.
9. Murphy, P. M. Chemokines and the molecular basis of cancer metastasis. N. Engl. J. Med., 2001, 345, 833-835.
10. Balkwill, F.: Cancer and the chemokine network. Nat. Rev. Cancer, 2004, 4, 540-550.
11. Dell'Agnola, C.; Biragyn, A. Clinical utilization of chemokines to combat cancer: the double-edged sword. Expert. Rev. Vaccines, 2007, 6, 267-283.
12. Farzan, M.; Babcock, G. J.; Vasilieva, N.; Wright, P. L.; Kiprilov, E.; Mirzabekov, T.; Choe, H. The role of post-translational modifications of the CXCR4 amino terminus in stromal-derived factor 1 alpha association and HIV-1 entry. J. Biol. Chem., 2002, 277, 29484-29489.
13. Hopkins, A. L.; Groom, C. R. The druggable genome. Nat. Rev. Drug Discov., 2002, 1, 727-730.
14. Liles, W. C.; Broxmeyer, H. E.; Rodger, E.; Wood, B.; Hubel, K.; Cooper, S.; Hangoc, G.; Bridger, G. J.; Henson, G. W.; Calandra, G.; Dale, D. C. Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. Blood, 2003, 102, 2728-2730.
15. Mosley, C. A.; Wilson, L. J.; Wiseman, J. M.; Skudlarek, J. W.; Liotta, D. C. Recent patents regarding the discovery of small molecule CXCR 4 antagonists. Expert Opin. Ther. Patents, 2009, 19, 23-38.
16. De Clercq, E. The bicyclam AMD3100 story. Nat. Rev. Drug Discov., 2003, 2, 581-587.
17. Horuk, R. Chemokine receptor antagonists: overcoming developmental hurdles. Nat. Rev. Drug Discov., 2009, 8, 23-33.
18. 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. USA, 2003, 100, 1603-1608.
19. Wells, J.; Arkin, M.; Braisted, A.; DeLano, W.; McDowell, B.; Oslob, J.; Raimundo, B.; Randal, M. Drug discovery at signaling interfaces. Ernst Schering Res. Found Workshop, 2003, 42, 19-27.
20. 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.
21. Hachet-Haas, M.; Balabanian, K.; Rohmer, F.; Pons, F.; Franchet, C.; Lecat, S.; Chow, K. Y.; Dagher, R.; Gizzi, P.; Didier, B.; Lagane, B.; Kellenberger, E.; Bonnet, D.; Baleux, F.; Haiech, J.; Parmentier, M.; Frossard, N.; Arenzana-Seisdedos, F.; Hibert, M.; Galzi, J. L. Small neutralizing molecules to inhibit actions of the chemokine CXCL12. J. Biol. Chem., 2008, 283, 23189-23199.
22. Galzi, J. L.; Hachet-Haas, M.; Bonnet, D.; Daubeuf, F.; Lecat, S.; Hibert, M.; Haiech, J.; Frossard, N. Neutralizing endogenous chemokines with small molecules Principles and potential therapeutic applications. Pharmacol. Ther., 2010, 126, 39-55.
23. Gasparik, V.; Daubeuf, F.; Hachet-Haas, M.; Rohmer, F.; Gizzi, P.; Haiech, J.; Galzi, J. L.; Hibert, M.; Bonnet, D.; Frossard, N. Prodrugs of a CXC chemokine-12 (CXCL12) neutraligand prevent inflammatory reactions in an asthma model in vivo. ACS Med. Chem. Lett., 2012, 3, 10-14.
24. Veldkamp, C. T.; Ziarek, J. J.; Peterson, F. C.; Chen, Y.; Volkman, B. F. Targeting SDF-1/CXCL12 with a ligand that prevents activation of CXCR4 through structure-based drug design. J. Am. Chem. Soc., 2010, 132, 7242-7243.
25. Wang, J.; Loberg, R.; Taichman, R. S. The pivotal role of CXCL12 (SDF-1)/CXCR4 axis in bone metastasis. Cancer Metastasis Rev., 2006, 25, 573-587.
26. Burger, J. A.; Stewart, D. J.; Wald, O.; Peled, A. Potential of CXCR4 antagonists for the treatment of metastatic lung cancer. Expert Rev. Anticancer Ther., 2011, 11, 621-630.
27. Nakashima, H.; Masuda, M.; Murakami, T.; Koyanagi, Y.; Matsumoto, A.; Fujii, N.; Yamamoto, N. Anti-human immunodeficiency virus activity of a novel synthetic peptide, T22 ([Tyr-5,12, Lys-7]polyphemusin II): a possible inhibitor of virus- cell fusion. Antimicrob. Agents Chemother., 1992, 36, 1249-1255.
28. Masuda, M.; Nakashima, H.; Ueda, T.; Naba, H.; Ikoma, R.; Otaka, A.; Terakawa, Y.; Tamamura, H.; Ibuka, T.; Murakami, T.; et al. A novel anti-HIV synthetic peptide, T-22 ([Tyr5,12,Lys7]- polyphemusin II). Biochem. Biophys. Res. Commun., 1992, 189, 845-850.
29. De Clercq, E.; Yamamoto, N.; Pauwels, R.; Baba, M.; Schols, D.; Nakashima, H.; Balzarini, J.; Debyser, Z.; Murrer, B. A.; Schwartz, D.; et al. Potent and selective inhibition of human immunodeficiency virus (HIV)-1 and HIV-2 replication by a class of bicyclams interacting with a viral uncoating event. Proc. Natl. Acad. Sci. USA, 1992, 89, 5286-5290.
30. De Clercq, E. The AMD3100 story: the path to the discovery of a stem cell mobilizer (Mozobil). Biochem. Pharmacol., 2009, 77, 1655-1664.
31. Doranz, B. J.; Grovit-Ferbas, K.; Sharron, M. P.; Mao, S. H.; Goetz, M. B.; Daar, E. S.; Doms, R. W.; O'Brien, W. A. A small- molecule inhibitor directed against the chemokine receptor CXCR4 prevents its use as an HIV-1 coreceptor. J. Exp. Med., 1997, 186, 1395-1400.
32. Schols, D.; Struyf, S.; Van Damme, J.; Este, J. A.; Henson, G.; De Clercq, E. Inhibition of T-tropic HIV strains by selective antagonization of the chemokine receptor CXCR4. J. Exp. Med., 1997, 186, 1383-1388.
33. Murakami, T.; Nakajima, T.; Koyanagi, Y.; Tachibana, K.; Fujii, N.; Tamamura, H.; Yoshida, N.; Waki, M.; Matsumoto, A.; Yoshie, O.; Kishimoto, T.; Yamamoto, N.; Nagasawa, T. A small molecule CXCR4 inhibitor that blocks T cell line-tropic HIV-1 infection. J. Exp. Med., 1997, 186, 1389-1393.
34. Tamamura, H.; Xu, Y.; Hattori, T.; Zhang, X.; Arakaki, R.; Kanbara, K.; Omagari, A.; Otaka, A.; Ibuka, T.; Yamamoto, N.; Nakashima, H.; Fujii, N. A low-molecular-weight inhibitor against the chemokine receptor CXCR4: a strong anti-HIV peptide T140. Biochem. Biophys. Res. Commun., 1998, 253, 877-882.
35. Tamamura, H.; Omagari, A.; Hiramatsu, K.; Gotoh, K.; Kanamoto, T.; Xu, Y.; Kodama, E.; Matsuoka, M.; Hattori, T.; Yamamoto, N.; Nakashima, H.; Otaka, A.; Fujii, N. Development of specific CXCR4 inhibitors possessing high selectivity indexes as well as complete stability in serum based on an anti-HIV peptide T140. Bioorg. Med. Chem. Lett., 2001, 11, 1897-1902.
36. Endres, M. J.; Clapham, P. R.; Marsh, M.; Ahuja, M.; Turner, J. D.; McKnight, A.; Thomas, J. F.; Stoebenau-Haggarty, B.; Choe, S.; Vance, P. J.; Wells, T. N.; Power, C. A.; Sutterwala, S. S.; Doms, R. W.; Landau, N. R.; Hoxie, J. A. CD4-independent infection by HIV-2 is mediated by fusin/CXCR4. Cell, 1996, 87, 745-756.
37. Bertolini, F.; Dell'Agnola, C.; Mancuso, P.; Rabascio, C.; Burlini, A.; Monestiroli, S.; Gobbi, A.; Pruneri, G.; Martinelli, G. CXCR4 neutralization, a novel therapeutic approach for non-Hodgkin's lymphoma. Cancer Res., 2002, 62, 3106-3112.
38. Engl, T.; Relja, B.; Marian, D.; Blumenberg, C.; Muller, I.; Beecken, W. D.; Jones, J.; Ringel, E. M.; Bereiter-Hahn, J.; Jonas, D.; Blaheta, R. A. CXCR4 chemokine receptor mediates prostate tumor cell adhesion through alpha5 and beta3 integrins. Neoplasia, 2006, 8, 290-301.
39. DiPersio, J. F.; Uy, G. L.; Yasothan, U.; Kirkpatrick, P. Plerixafor. Nat. Rev. Drug Discov., 2009, 8, 105-106.
40. Kofuku, Y.; Yoshiura, C.; Ueda, T.; Terasawa, H.; Hirai, T.; Tominaga, S.; Hirose, M.; Maeda, Y.; Takahashi, H.; Terashima, Y.; Matsushima, K.; Shimada, I. Structural basis of the interaction between chemokine stromal cell-derived factor-1/CXCL12 and its G-protein-coupled receptor CXCR4. J. Biol. Chem., 2009, 284, 35240-35250.
41. Liang, Z.; Zhan, W.; Zhu, A.; Yoon, Y.; Lin, S.; Sasaki, M.; Klapproth, J. M.; Yang, H.; Grossniklaus, H. E.; Xu, J.; Rojas, M.; Voll, R. J.; Goodman, M. M.; Arrendale, R. F.; Liu, J.; Yun, C. C.; Snyder, J. P.; Liotta, D. C.; Shim, H. Development of a unique small molecule modulator of CXCR4. PLoS One, 2012, 7, e34038.
42. Zhan, W.; Liang, Z.; Zhu, A.; Kurtkaya, S.; Shim, H.; Snyder, J. P.; Liotta, D. C. Discovery of small molecule CXCR4 antagonists. J. Med. Chem., 2007, 50, 5655-5664.
43. Zhu, A.; Zhan, W.; Liang, Z.; Yoon, Y.; Yang, H.; Grossniklaus, H. E.; Xu, J.; Rojas, M.; Lockwood, M.; Snyder, J. P.; Liotta, D. C.; Shim, H. Dipyrimidine amines: a novel class of chemokine receptor type 4 antagonists with high specificity. J. Med. Chem., 2010, 53, 8556-8568.
44. Bridger, G. J.; Skerlj, R. T.; Hernandez-Abad, P. E.; Bogucki, D. E.; Wang, Z.; Zhou, Y.; Nan, S.; Boehringer, E. M.; Wilson, T.; Crawford, J.; Metz, M.; Hatse, S.; Princen, K.; De Clercq, E.; Schols, D. Synthesis and structure-activity relationships of azamacrocyclic C-X-C chemokine receptor 4 antagonists: analogues containing a single azamacrocyclic ring are potent inhibitors of T-cell tropic (X4) HIV-1 replication. J. Med. Chem., 2010, 53, 1250-1260.
45. Skerlj, R. T.; Bridger, G. J.; Kaller, A.; McEachern, E. J.; Crawford, J. B.; Zhou, Y.; Atsma, B.; Langille, J.; Nan, S.; Veale, D.; Wilson, T.; Harwig, C.; Hatse, S.; Princen, K.; De Clercq, E.; Schols, D. Discovery of novel small molecule orally bioavailable C-X-C chemokine receptor 4 antagonists that are potent inhibitors of T-tropic (X4) HIV-1 replication. J. Med. Chem., 2010, 53, 3376-3388.
46. Thoma, G.; Streiff, M. B.; Kovarik, J.; Glickman, F.; Wagner, T.; Beerli, C.; Zerwes, H. G. Orally bioavailable isothioureas block function of the chemokine receptor CXCR4 in vitro and in vivo. J. Med. Chem., 2008, 51, 7915-7920.
47. Wu, B.; Chien, E. Y.; Mol, C. D.; Fenalti, G.; Liu, W.; Katritch, V.; Abagyan, R.; Brooun, A.; Wells, P.; Bi, F. C.; Hamel, D. J.; Kuhn, P.; Handel, T. M.; Cherezov, V.; Stevens, R. C. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science, 2010, 330, 1066-1071.
48. Sun, X.; Cheng, G.; Hao, M.; Zheng, J.; Zhou, X.; Zhang, J.; Taichman, R. S.; Pienta, K. J.; Wang, J. CXCL12/CXCR4/CXCR7 chemokine axis and cancer progression. Cancer Metastasis Rev., 2010, 29, 709-722.
49. Horuk, R. Chemokine receptor antagonists: overcoming developmental hurdles. Nat. Rev. Drug Discov., 2009, 8, 23-33.
50. Crump, M. P.; Gong, J. H.; Loetscher, P.; Rajarathnam, K.; Amara, A.; Arenzana-Seisdedos, F.; Virelizier, J. L.; Baggiolini, M.; Sykes, B. D.; Clark-Lewis, I. Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1. Embo J., 1997, 16, 6996-7007.
51. Gayle, R. B., 3rd; Sleath, P. R.; Srinivason, S.; Birks, C. W.; Weerawarna, K. S.; Cerretti, D. P.; Kozlosky, C. J.; Nelson, N.; Vanden Bos, T.; Beckmann, M. P. Importance of the amino terminus of the interleukin-8 receptor in ligand interactions. J. Biol. Chem., 1993, 268, 7283-7289.
52. Mizoue, L. S.; Bazan, J. F.; Johnson, E. C.; Handel, T. M. Solution structure and dynamics of the CX3C chemokine domain of fractalkine and its interaction with an N-terminal fragment of CX3CR1. Biochemistry, 1999, 38, 1402-1414.
53. Doranz, B. J.; Orsini, M. J.; Turner, J. D.; Hoffman, T. L.; Berson, J. F.; Hoxie, J. A.; Peiper, S. C.; Brass, L. F.; Doms, R. W. Identification of CXCR4 domains that support coreceptor and chemokine receptor functions. J. Virol., 1999, 73, 2752-2761.
54. Farzan, M.; Mirzabekov, T.; Kolchinsky, P.; Wyatt, R.; Cayabyab, M.; Gerard, N. P.; Gerard, C.; Sodroski, J.; Choe, H. Tyrosine sulfation of the amino terminus of CCR5 facilitates HIV-1 entry. Cell, 1999, 96, 667-676.
55. Fong, A. M.; Alam, S. M.; Imai, T.; Haribabu, B.; Patel, D. D. CX3CR1 tyrosine sulfation enhances fractalkine-induced cell adhesion. J. Biol. Chem., 2002, 277, 19418-19423.
56. Seibert, C.; Cadene, M.; Sanfiz, A.; Chait, B. T.; Sakmar, T. P. Tyrosine sulfation of CCR5 N-terminal peptide by tyrosylprotein sulfotransferases 1 and 2 follows a discrete pattern and temporal sequence. Proc. Natl. Acad. Sci. USA, 2002, 99, 11031-11036.
57. Veldkamp, C. T.; Seibert, C.; Peterson, F. C.; Sakmar, T. P.; Volkman, B. F. Recognition of a CXCR4 sulfotyrosine by the chemokine stromal cell-derived factor-1alpha (SDF- 1alpha/CXCL12). J. Mol. Biol., 2006, 359, 1400-1409.
58. Seibert, C.; Veldkamp, C. T.; Peterson, F. C.; Chait, B. T.; Volkman, B. F.; Sakmar, T. P. Sequential tyrosine sulfation of CXCR4 by tyrosylprotein sulfotransferases. Biochemistry, 2008, 47, 11251-11262.
59. Colvin, R. A.; Campanella, G. S.; Manice, L. A.; Luster, A. D. CXCR3 requires tyrosine sulfation for ligand binding and a second extracellular loop arginine residue for ligand-induced chemotaxis. Mol. Cell Biol., 2006, 26, 5838-5849.
60. Preobrazhensky, A. A.; Dragan, S.; Kawano, T.; Gavrilin, M. A.; Gulina, I. V.; Chakravarty, L.; Kolattukudy, P. E. Monocyte chemotactic protein-1 receptor CCR2B is a glycoprotein that has tyrosine sulfation in a conserved extracellular N-terminal region. J. Immunol., 2000, 165, 5295-5303.
61. Simpson, L. S.; Zhu, J. Z.; Widlanski, T. S.; Stone, M. J. Regulation of chemokine recognition by site-specific tyrosine sulfation of receptor peptides. Chem. Biol., 2009, 16, 153-161.
62. Farzan, M.; Chung, S.; Li, W.; Vasilieva, N.; Wright, P. L.; Schnitzler, C. E.; Marchione, R. J.; Gerard, C.; Gerard, N. P.; Sodroski, J.; Choe, H. Tyrosine-sulfated peptides functionally reconstitute a CCR5 variant lacking a critical amino-terminal region. J. Biol. Chem., 2002, 277, 40397-40402.
63. Carlsson, J.; Coleman, R. G.; Setola, V.; Irwin, J. J.; Fan, H.; Schlessinger, A.; Sali, A.; Roth, B. L.; Shoichet, B. K. Ligand discovery from a dopamine D3 receptor homology model and crystal structure. Nat. Chem. Biol., 2011, 7, 769-778.
64. Veldkamp, C. T.; Seibert, C.; Peterson, F. C.; De la Cruz, N. B.; Haugner, J. C., 3rd; Basnet, H.; Sakmar, T. P.; Volkman, B. F. Structural basis of CXCR4 sulfotyrosine recognition by the chemokine SDF-1/CXCL12. Sci. Signal, 2008, 1, ra4.
65. Ziarek, J. J.; Heroux, M. S.; Veldkamp, C. T.; Peterson, F. C.; Volkman, B. F. Sulfotyrosine recognition as marker for druggable sites in the extracellular space. Inter. J. Mol. Sci., 2011, 12, 3740-3756.
66. Danan, L. M.; Yu, Z.; Ludden, P. J.; Jia, W.; Moore, K. L.; Leary, J. A. Catalytic Mechanism of Golgi-Resident Human Tyrosylprotein Sulfotransferase-2: A Mass Spectrometry Approach. J. Am. Soc. Mass Spectrom., 2010., 21, 1633-1642.
67. Hajduk, P. J. Fragment-based drug design: how big is too big? J. Med. Chem., 2006, 49, 6972-6976.
68. Wells, J. A.; McClendon, C. L. Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature, 2007, 450, 1001-1009.
69. Herr, R. J. 5-Substituted-1H-tetrazoles as carboxylic acid isosteres: medicinal chemistry and synthetic methods. Bioorg. Med. Chem., 2002, 10, 3379-3393.
70. Biot, C.; Bauer, H.; Schirmer, R. H.; Davioud-Charvet, E. 5-substituted tetrazoles as bioisosteres of carboxylic acids. Bioisosterism and mechanistic studies on glutathione reductase inhibitors as antimalarials. J. Med. Chem., 2004, 47, 5972-5983.
71. Pegklidou, K.; Koukoulitsa, C.; Nicolaou, I.; Demopoulos, V. J. Design and synthesis of novel series of pyrrole based chemotypes and their evaluation as selective aldose reductase inhibitors. A case of bioisosterism between a carboxylic acid moiety and that of a tetrazole. Bioorg. Med. Chem., 2010, 18, 2107-2114.
72. Roh, J.; Artamonova, T. V.; Vavrova, K.; Koldobskii, G. I.; Hrabalek, A. Practical synthesis of 5-substituted tetrazoles under microwave irradiation. Synthesis, 2009, 2175-2178.
73. Veldkamp, C. T.; Peterson, F. C.; Pelzek, A. J.; Volkman, B. F. The monomer-dimer equilibrium of stromal cell-derived factor-1 (CXCL 12) is altered by pH, phosphate, sulfate, and heparin. Protein Sci., 2005, 14, 1071-1081.
74. Delaglio, F.; Grzesiek, S.; Vuister, G. W.; Zhu, G.; Pfeifer, J.; Bax, A. NMRPipe: a multidimensional spectral processing system based on UNIX pipes. J. Biomol. NMR, 1995, 6, 277-293.
75. Keller, R. The Computer-Aided Resonance Assignment Tutorial, Cantina Verlag: Goldau, 2004.
76. Burns, J. M.; Summers, B. C.; Wang, Y.; Melikian, A.; Berahovich, R.; Miao, Z.; Penfold, M. E.; Sunshine, M. J.; Littman, D. R.; Kuo, C. J.; Wei, K.; McMaster, B. E.; Wright, K.; Howard, M. C.; Schall, T. J. A novel chemokine receptor for SDF-1 and I- TAC involved in cell survival, cell adhesion, and tumor development. J. Exp. Med., 2006, 203, 2201-2213.
77. Miao, Z.; Luker, K. E.; Summers, B. C.; Berahovich, R.; Bhojani, M. S.; Rehemtulla, A.; Kleer, C. G.; Essner, J. J.; Nasevicius, A.; Luker, G. D.; Howard, M. C.; Schall, T. J. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc. Natl. Acad. Sci. USA, 2007, 104, 15735-15740.
78. Luker, K. E.; Lewin, S. A.; Mihalko, L. A.; Schmidt, B. T.; Winkler, J. S.; Coggins, N. L.; Thomas, D. G.; Luker, G. D. Scavenging of CXCL12 by CXCR7 promotes tumor growth and metastasis of CXCR4-positive breast cancer cells. Oncogene, 2012, 31, 4750-4758.
79. Kalatskaya, I.; Berchiche, Y. A.; Gravel, S.; Limberg, B. J.; Rosenbaum, J. S.; Heveker, N. AMD3100 is a CXCR7 ligand with allosteric agonist properties. Mol. Pharmacol., 2009, 75, 1240-1247.
80. Gravel, S.; Malouf, C.; Boulais, P. E.; Berchiche, Y. A.; Oishi, S.; Fujii, N.; Leduc, R.; Sinnett, D.; Heveker, N. The peptidomimetic CXCR4 antagonist TC14012 recruits beta-arrestin to CXCR7: roles of receptor domains. J. Biol. Chem., 2010, 285, 37939-37943.
81. Mysinger, M. M.; Weiss, D. R.; Ziarek, J. J.; Gravel, S.; Doak, A K.; Karpiak, J.; Heveker, N.; Shoichet, B. K.; Volkman, B. F. Structure-based ligand discovery for the protein-protein interface of chemokine receptor CXCR4. Proc. Natl. Acad. Sci. USA, 2012, 109, 5517-5522.
82. Liu, J.; Louie, S.; Hsu, W.; Yu, K. M.; Nicholas, H. B., Jr.; Rosenquist, G. L. Tyrosine sulfation is prevalent in human chemokine receptors important in lung disease. Am. J. Respir. Cell Mol. Biol., 2008, 38, 738-743.
83. Hemmerich, S.; Paavola, C.; Bloom, A.; Bhakta, S.; Freedman, R.; Grunberger, D.; Krstenansky, J.; Lee, S.; McCarley, D.; Mulkins, M.; Wong, B.; Pease, J.; Mizoue, L.; Mirzadegan, T.; Polsky, I.; Thompson, K.; Handel, T. M.; Jarnagin, K. Identification of residues in the monocyte chemotactic protein-1 that contact the MCP-1 receptor, CCR2. Biochemistry, 1999, 38, 13013-13025.
84. Clubb, R. T.; Omichinski, J. G.; Clore, G. M.; Gronenborn, A. M. Mapping the binding surface of interleukin-8 complexed with an N-terminal fragment of the type 1 human interleukin-8 receptor. FEBS Lett., 1994, 338, 93-97.
85. Mizoue, L. S.; Sullivan, S. K.; King, D. S.; Kledal, T. N.; Schwartz, T. W.; Bacon, K. B.; Handel, T. M. Molecular determinants of receptor binding and signaling by the CX3C chemokine fractalkine. J. Biol. Chem., 2001, 276, 33906-33914.
86. Saini, V.; Marchese, A.; Majetschak, M. CXC chemokine receptor 4 is a cell surface receptor for extracellular ubiquitin. J. Biol. Chem., 2010, 285, 15566-15576.
87. Bernhagen, J.; Krohn, R.; Lue, H.; Gregory, J. L.; Zernecke, A.; Koenen, R. R.; Dewor, M.; Georgiev, I.; Schober, A.; Leng, L.; Kooistra, T.; Fingerle-Rowson, G.; Ghezzi, P.; Kleemann, R.; McColl, S. R.; Bucala, R.; Hickey, M. J.; Weber, C. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat. Med., 2007, 13, 587-596.
88. Kohout, T. A.; Nicholas, S. L.; Perry, S. J.; Reinhart, G.; Junger, S.; Struthers, R. S. Differential desensitization, receptor phosphorylation, beta-arrestin recruitment, and ERK1/2 activation by the two endogenous ligands for the CC chemokine receptor 7. J. Biol. Chem., 2004, 279, 23214-23222.
89. Zidar, D. A.; Violin, J. D.; Whalen, E. J.; Lefkowitz, R. J. Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands. Proc. Natl. Acad. Sci. USA, 2009, 106, 9649-9654.
90. Drury, L. J.; Ziarek, J. J.; Gravel, S.; Veldkamp, C. T.; Takekoshi, T.; Hwang, S. T.; Heveker, N.; Volkman, B. F.; Dwinell, M. B. Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways. Proc. Natl. Acad. Sci. USA, 2011, 108, 17655-17660.
91. Roy, P.P.; Roy, K. Molecular docking and QSAR studies of aromatase inhibitor androstenedione derivatives. J. Pharm. Pharmacol., 2010, 62, 1717-1728.
92. Mitra, I.; Saha, A.; Roy, K. Chemometric modeling of free radical scavenging activity of flavone derivatives. Eur. J. Med. Chem., 2010, 45, 5071-5079.
93. Roy, K.K.; Singh, S.; Saxena, A.K. Integration-mediated prediction enrichment of quantitative model for Hsp90 inhibitors as anti- cancer agents: 3D-QSAR study. Mol. Divers., 2011, 15, 477-489.
94. Pisco, L.; Kordian, M.; Peseke, K.; Feist, H.; Michalik, D.; Estrada, E.; Carvalho, J.; Hamilton, G.; Rando, D.; Quincoces, J. Synthesis of compounds with antiproliferative activity as analogues of prenylated natural products existing in Brazilian propolis. Eur. J. Med. Chem., 2006, 41, 401-407.
95. Estrada, E.; Uriarte, E.; Molina, E.; Simon-Manso, Y.; Milne, G.W. An integrated in silico analysis of drug-binding to human serum albumin. J. Chem. Inf. Model., 2006, 46, 2709-2724.
96. Estrada, E.; Quincoces, J.A.; Patlewicz, G. Creating molecular diversity from antioxidants in Brazilian propolis. Combination of TOPS-MODE QSAR and virtual structure generation. Mol. Divers., 2004, 8, 21-33.
97. Estrada, E.; Vilar, S.; Uriarte, E.; Gutierrez, Y. In silico studies toward the discovery of new anti-HIV nucleoside compounds with the use of TOPS-MODE and 2D/3D connectivity indices. 1. Pyrimidyl derivatives. J. Chem. Inf. Comput. Sci., 2002, 42, 1194-1203.
98. Estrada, E.; Uriarte, E.; Montero, A.; Teijeira, M.; Santana, L.; De Clercq, E. A novel approach for the virtual screening and rational design of anticancer compounds. J. Med. Chem., 2000, 43, 1975-1985.
99. Speck-Planche, A.; Luan, F.; Cordeiro, M.N. Discovery of anti-Alzheimer agents: current ligand-based approaches toward the design of acetylcholinesterase inhibitors. Mini Rev. Med. Chem., 2012, 12, 583-591.
100. Speck-Planche, A.; Kleandrova, V.V. QSAR and molecular docking techniques for the discovery of potent monoamine oxidase B inhibitors: Computer-aided generation of new rasagiline bioisosteres. Curr. Top. Med. Chem., 2012, 12, 1734-1747.
101. Speck-Planche, A.; Cordeiro, M.N. Computer-aided drug design methodologies toward the design of anti-hepatitis C agents. Curr. Top. Med. Chem., 2012, 12, 802-813.
102. Speck-Planche, A.; Guilarte-Montero, L.; Yera-Bueno, R.; Rojas-Vargas, J.A.; Garcia-Lopez, A.; Uriarte, E.; Molina-Perez, E. Rational design of new agrochemical fungicides using substructural descriptors. Pest Manag. Sci., 2011, 67, 438-445.
103. Speck-Planche, A.; Cordeiro, M.N.; Guilarte-Montero, L.; Yera-Bueno, R. Current computational approaches towards the rational design of new insecticidal agents. Curr. Comput. Aided Drug Des., 2011, 7, 304-314.
104. Speck-Planche, A.; Cordeiro, M.N. Current drug design of anti-HIV agents through the inhibition of C-C chemokine receptor type 5. Curr. Comput. Aided Drug Des., 2011, 7, 238-248.
105. Speck-Planche, A.; Scotti, M.T.; Emerenciano, V.P.; García-López, A.; Molina-Pérez, E.; Uriarte, E. Designing novel antitrypanosomal agents from a mixed graph-theoretical substructural approach. J. Comput. Chem., 2010, 31, 882-894.
106. Speck-Planche, A.; Scotti, M.T.; de Paulo-Emerenciano, V. Current pharmaceutical design of antituberculosis drugs: future perspectives. Curr. Pharm. Des., 2010, 16, 2656-2665.
107. Speck-Planche, A.; Scotti, M.T.; García-López, A.; Emerenciano, V.P.; Molina-Pérez, E.; Uriarte, E. Design of novel antituberculosis compounds using graph-theoretical and substructural approaches. Mol. Divers., 2009, 13, 445-458.
108. Rescigno, A.; Casanola-Martin, G.M.; Sanjust, E.; Zucca, P.; Marrero-Ponce, Y. Vanilloid derivatives as tyrosinase inhibitors driven by virtual screening-based QSAR models. Drug Test. Anal., 2011, 3, 176-181.
109. Marrero-Ponce, Y.; Siverio-Mota, D.; Galvez-Llompart, M.; Recio, M.C.; Giner, R.M.; Garcia-Domenech, R.; Torrens, F.; Aran, V.J.; Cordero-Maldonado, M.L.; Esguera, C.V.; de Witte, P.A.; Crawford, A.D. Discovery of novel anti-inflammatory drug-like compounds by aligning in silico and in vivo screening: the nitroindazolinone chemotype. Eur. J. Med. Chem., 2011, 46, 5736- 5753.
110. Le-Thi-Thu, H.; Casanola-Martin, G.M.; Marrero-Ponce, Y.; Rescigno, A.; Saso, L.; Parmar, V.S.; Torrens, F.; Abad, C. Novel coumarin-based tyrosinase inhibitors discovered by OECD principles-validated QSAR approach from an enlarged, balanced database. Mol. Divers., 2011, 15, 507-520.
111. Casañola-Martin, G.M.; Marrero-Ponce, Y.; Khan, M.T.; Khan, S.B.; Torrens, F.; Perez-Jimenez, F.; Rescigno, A.; Abad, C. Bond- based 2D quadratic fingerprints in QSAR studies: virtual and in vitro tyrosinase inhibitory activity elucidation. Chem. Biol. Drug Des., 2010, 76, 538-545.
112. Meneses-Marcel, A.; Rivera-Borroto, O.M.; Marrero-Ponce, Y.; Montero, A.; Machado Tugores, Y.; Escario, J.A.; Gomez Barrio, A.; Montero Pereira, D.; Nogal, J.J.; Kouznetsov, V.V.; Ochoa Puentes, C.; Bohorquez, A.R.; Grau, R.; Torrens, F.; Ibarra- Velarde, F.; Aran, V.J. New antitrichomonal drug-like chemicals selected by bond (edge)-based TOMOCOMD-CARDD descriptors. J. Biomol. Screen., 2008, 13, 785-794.
113. Marrero-Ponce, Y.; Meneses-Marcel, A.; Rivera-Borroto, O.M.; Garcia-Domenech, R.; De Julian-Ortiz, J.V.; Montero, A.; Escario, J.A.; Barrio, A.G.; Pereira, D.M.; Nogal, J.J.; Grau, R.; Torrens, F.; Vogel, C.; Aran, V.J. Bond-based linear indices in QSAR: computational discovery of novel anti-trichomonal compounds. J. Comput. Aided Mol. Des., 2008, 22, 523-540.
114. Gonzalez-Diaz, H.; Dea-Ayuela, M.A.; Perez-Montoto, L.G.; Prado-Prado, F.J.; Aguero-Chapin, G.; Bolas-Fernandez, F.; Vazquez-Padron, R.I.; Ubeira, F.M. QSAR for RNases and theoretic-experimental study of molecular diversity on peptide mass fingerprints of a new Leishmania infantum protein. Mol. Divers., 2010, 14, 349-369.
115. Perez-Bello, A.; Munteanu, C.R.; Ubeira, F.M.; De Magalhaes, A.L.; Uriarte, E.; Gonzalez-Diaz, H. Alignment-free prediction of mycobacterial DNA promoters based on pseudo-folding lattice network or star-graph topological indices. J. Theor. Biol., 2009, 256, 458-466.
116. Santana, L.; Gonzalez-Diaz, H.; Quezada, E.; Uriarte, E.; Yanez, M.; Vina, D.; Orallo, F. Quantitative structure-activity relationship and complex network approach to monoamine oxidase A and B inhibitors. J. Med. Chem., 2008, 51, 6740-6751.
117. Munteanu, C.R.; Gonzalez-Diaz, H.; Magalhaes, A.L. Enzymes/non-enzymes classification model complexity based on composition, sequence, 3D and topological indices. J. Theor. Biol., 2008, 254, 476-482.
118. Dea-Ayuela, M.A.; Perez-Castillo, Y.; Meneses-Marcel, A.; Ubeira, F.M.; Bolas-Fernandez, F.; Chou, K.C.; Gonzalez-Diaz, H. HP-Lattice QSAR for dynein proteins: experimental proteomics (2D-electrophoresis, mass spectrometry) and theoretic study of a Leishmania infantum sequence. Bioorg. Med. Chem., 2008, 16, 7770-7776.
119. Gonzalez-Diaz, H.; Bonet, I.; Teran, C.; De Clercq, E.; Bello, R.; Garcia, M.M.; Santana, L.; Uriarte, E. ANN-QSAR model for selection of anticancer leads from structurally heterogeneous series of compounds. Eur. J. Med. Chem., 2007, 42, 580-585.
120. Speck-Planche, A.; Luan, F.; Cordeiro, M.N. Role of ligand-based drug design methodologies toward the discovery of new anti-Alzheimer agents: futures perspectives in Fragment-Based Ligand Design. Curr. Med. Chem., 2012, 19, 1635-1645.
121. Speck-Planche, A.; Kleandrova, V.V.; Scotti, M.T. Fragment-based approach for the in silico discovery of multi-target insecticides. Chemometr. Intell. Lab. Syst., 2012, 111, 39-45.
122. Speck-Planche, A.; Kleandrova, V.V.; Luan, F.; Cordeiro, M.N. Chemoinformatics in multi-target drug discovery for anti-cancer therapy: in silico design of potent and versatile anti-brain tumor agents. Anticancer Agents Med. Chem., 2012, 12, 678-685.
123. Speck-Planche, A.; Kleandrova, V.V.; Luan, F.; Cordeiro, M.N. Predicting multiple ecotoxicological profiles in agrochemical fungicides: a multi-species chemoinformatic approach. Ecotoxicol. Environ. Saf., 2012, 80, 308-313.
124. Speck-Planche, A.; Kleandrova, V.V.; Luan, F.; Cordeiro, M.N. Chemoinformatics in anti-cancer chemotherapy: multi-target QSAR model for the in silico discovery of anti-breast cancer agents. Eur. J. Pharm. Sci., 2012, 47, 273-279.
125. Speck-Planche, A.; Kleandrova, V.V.; Luan, F.; Cordeiro, M.N. A ligand-based approach for the in silico discovery of multi-target inhibitors for proteins associated with HIV infection. Mol. Biosyst., 2012, 8, 2188-2196.
126. Speck-Planche, A.; Kleandrova, V.V.; Luan, F.; Cordeiro, M.N. Rational drug design for anti-cancer chemotherapy: multi-target QSAR models for the in silico discovery of anti-colorectal cancer agents. Bioorg. Med. Chem., 2012, 20, 4848-4855.
127. Speck-Planche, A.; Kleandrova, V.V. In silico design of multi-target inhibitors for C-C chemokine receptors using substructural descriptors. Mol. Divers., 2012, 16, 183-191.
128. Speck-Planche, A.; Kleandrova, V.V.; Rojas-Vargas, J.A. QSAR model toward the rational design of new agrochemical fungicides with a defined resistance risk using substructural descriptors. Mol. Divers., 2011, 15, 901-909.
129. Speck-Planche, A.; Kleandrova, V.V.; Luan, F.; Cordeiro, M.N. Multi-target drug discovery in anti-cancer therapy: fragment-based approach toward the design of potent and versatile anti-prostate cancer agents. Bioorg. Med. Chem., 2011, 19, 6239-6244.
130. Speck-Planche, A.; Kleandrova, V.V.; Luan, F.; Cordeiro, M.N. Fragment-based QSAR model toward the selection of versatile anti-sarcoma leads. Eur. J. Med. Chem., 2011, 46, 5910-5916.
131. Tenorio-Borroto, E.; Penuelas Rivas, C.G.; Vasquez Chagoyan, J.C.; Castanedo, N.; Prado-Prado, F.J.; Garcia-Mera, X.; Gonzalez- Diaz, H. ANN multiplexing model of drugs effect on macrophages; theoretical and flow cytometry study on the cytotoxicity of the anti- microbial drug G1 in spleen. Bioorg. Med. Chem., 2012, 20, 6181- 6194.
132. Prado-Prado, F.J.; Garcia-Mera, X.; Gonzalez-Diaz, H. Multi-target spectral moment QSAR versus ANN for antiparasitic drugs against different parasite species. Bioorg. Med. Chem., 2010, 18, 2225-2231.
133. Perez-Montoto, L.G.; Santana, L.; Gonzalez-Diaz, H. Scoring function for DNA-drug docking of anticancer and antiparasitic compounds based on spectral moments of 2D lattice graphs for molecular dynamics trajectories. Eur. J. Med. Chem., 2009, 44, 4461-4469.
134. Munteanu, C.R.; Magalhaes, A.L.; Uriarte, E.; Gonzalez-Diaz, H. Multi-target QPDR classification model for human breast and colon cancer-related proteins using star graph topological indices. J. Theor. Biol., 2009, 257, 303-311.
135. Concu, R.; Dea-Ayuela, M.A.; Perez-Montoto, L.G.; Prado-Prado, F.J.; Uriarte, E.; Bolas-Fernandez, F.; Podda, G.; Pazos, A.; Munteanu, C.R.; Ubeira, F.M.; Gonzalez-Diaz, H. 3D entropy and moments prediction of enzyme classes and experimental-theoretic study of peptide fingerprints in Leishmania parasites. Biochim. Biophys. Acta, 2009, 1794, 1784-1794.
136. Concu, R.; Dea-Ayuela, M.A.; Perez-Montoto, L.G.; Bolas-Fernandez, F.; Prado-Prado, F.J.; Podda, G.; Uriarte, E.; Ubeira, F.M.; Gonzalez-Diaz, H. Prediction of enzyme classes from 3D structure: a general model and examples of experimental-theoretic scoring of peptide mass fingerprints of Leishmania proteins. J. Proteome Res., 2009, 8, 4372-4382.
137. Prado-Prado, F.J.; Gonzalez-Diaz, H.; de la Vega, O.M.; Ubeira, F.M.; Chou, K.C. Unified QSAR approach to antimicrobials. Part 3: first multi-tasking QSAR model for input-coded prediction, structural back-projection, and complex networks clustering of antiprotozoal compounds. Bioorg. Med. Chem., 2008, 16, 5871- 5880.
138. Speck-Planche, A.; Kleandrova, V.V.; Luan, F.; Cordeiro, M.N. In silico discovery and virtual screening of multi-target inhibitors for proteins in Mycobacterium tuberculosis. Comb. Chem. High Throughput Screen., 2012, 15, 666-673.
139. Speck-Planche, A.; Cordeiro, M.N.D.S. Application of Bioinformatics for the search of novel anti-viral therapies: Rational design of anti-herpes agents. Curr. Bioinform., 2011, 6, 81-93.
140. Prado-Prado, F.; Garcia-Mera, X.; Abeijon, P.; Alonso, N.; Caamano, O.; Yanez, M.; Garate, T.; Mezo, M.; Gonzalez-Warleta, M.; Muino, L.; Ubeira, F.M.; Gonzalez-Diaz, H. Using entropy of drug and protein graphs to predict FDA drug-target network: theoretic-experimental study of MAO inhibitors and hemoglobin peptides from Fasciola hepatica. Eur. J. Med. Chem., 2011, 46, 1074-1094.
141. Gonzalez-Diaz, H.; Prado-Prado, F.; Sobarzo-Sanchez, E.; Haddad, M.; Maurel Chevalley, S.; Valentin, A.; Quetin-Leclercq, J.; Dea-Ayuela, M.A.; Teresa Gomez-Munos, M.; Munteanu, C.R.; Jose Torres-Labandeira, J.; Garcia-Mera, X.; Tapia, R.A.; Ubeira, F.M. NL MIND-BEST: A web server for ligands and proteins discovery- Theoretic-experimental study of proteins of Giardia lamblia and new compounds active against Plasmodium falciparum. J. Theor. Biol., 2011, 276, 229-249.
142. Gonzalez-Diaz, H.; Prado-Prado, F.; Garcia-Mera, X.; Alonso, N.; Abeijon, P.; Caamano, O.; Yanez, M.; Munteanu, C.R.; Pazos, A.; Dea-Ayuela, M.A.; Gomez-Munoz, M.T.; Garijo, M.M.; Sansano, J.; Ubeira, F.M. MIND-BEST: Web Server for Drugs and Target Discovery; Design, Synthesis, and Assay of MAO-B Inhibitors and Theoretical-Experimental Study of G3PDH Protein from Trichomonas gallinae. J. Proteome Res., 2011, 10, 1698-1718.
143. Vina, D.; Uriarte, E.; Orallo, F.; Gonzalez-Diaz, H. Alignment-free prediction of a drug-target complex network based on parameters of drug connectivity and protein sequence of receptors. Mol. Pharm., 2009, 6, 825-835.
144. Estrada, E. Generalized walks-based centrality measures for complex biological networks. J. Theor. Biol., 2010, 263, 556-565.
145. Estrada, E. Universality in protein residue networks. Biophys. J., 2010, 98, 890-900.
146. Estrada, E.; Hatano, N. Communicability in complex networks. Phys. Rev. E Stat. Nonlin. Soft Matter Phys., 2008, 77, 036111.
147. Estrada, E.; Bodin, O. Using network centrality measures to manage landscape connectivity. Ecol. Appl., 2008, 18, 1810-1825.
148. Gonzalez-Diaz, H. Network topological indices, drug metabolism, and distribution. Curr. Drug Metab., 2010, 11, 283-284.
149. Vilar, S.; Gonzalez-Diaz, H.; Santana, L.; Uriarte, E. A network- QSAR model for prediction of genetic-component biomarkers in human colorectal cancer. J. Theor. Biol., 2009, 261, 449-458.
150. Prado-Prado, F.J.; Uriarte, E.; Borges, F.; Gonzalez-Diaz, H. Multi-target spectral moments for QSAR and Complex Networks study of antibacterial drugs. Eur. J. Med. Chem., 2009, 44, 4516-4521.
151. Prado-Prado, F.J.; Ubeira, F.M.; Borges, F.; Gonzalez-Diaz, H. Unified QSAR & network-based computational chemistry approach to antimicrobials. II. Multiple distance and triadic census analysis of antiparasitic drugs complex networks. J. Comput. Chem., 2009, 31, 164-173.
152. Prado-Prado, F.J.; Martinez de laVega, O.; Uriarte, E.; Ubeira, F.M.; Chou, K.C.; Gonzalez-Diaz, H. Unified QSAR approach to antimicrobials. 4. Multi-target QSAR modeling and comparative multi-distance study of the giant components of antiviral drug-drug complex networks. Bioorg. Med. Chem., 2009, 17, 569-575