Comparison of ligand-based and receptor-based virtual screening of HIV entry inhibitors for the CXCR4 and CCR5 receptors using 3D ligand shape matching and ligand-receptor docking

Journal of Chemical Information and Modeling

Volumn 48, Issue 3, 2008, Pages 509-533

  Përez Nueno, Violeta I ^a   Ritchie, David W ^b   Rabal, Obdulia ^a   Pascual, Rosalia ^a   Borrella, Jose I ^a   Teixidó, Jordi ^a  

^a INSTITUT QUÍMIC DE SARRIÀ   (Spain)

^b UNIVERSITY OF ABERDEEN   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

DOCKING; LIGANDS; PROTEINS; VIRTUAL REALITY; VIRUSES;

CELL FUSION; SHAPE MATCHING;

MEDICAL PROBLEMS;

CHEMOKINE RECEPTOR CCR5; CHEMOKINE RECEPTOR CXCR4; CXCR4 PROTEIN, HUMAN; HUMAN IMMUNODEFICIENCY VIRUS FUSION INHIBITOR; LIGAND;

AMINO ACID SEQUENCE; ANIMAL; ARTICLE; BINDING SITE; CATTLE; CHEMISTRY; COMPARATIVE STUDY; DRUG ANTAGONISM; MOLECULAR GENETICS; SEQUENCE HOMOLOGY;

AMINO ACID SEQUENCE; ANIMALS; BINDING SITES; CATTLE; HIV FUSION INHIBITORS; LIGANDS; MOLECULAR SEQUENCE DATA; RECEPTORS, CCR5; RECEPTORS, CXCR4; SEQUENCE HOMOLOGY, AMINO ACID;

EID: 42149089443     PISSN: 15499596     EISSN: 1549960X     Source Type: Journal    
DOI: 10.1021/ci700415g     Document Type: Article

References (126)

1. World Health Organisation AIDS Update 2006, http://www.who.int/hiv/en/ (accessed Dec. 23, 2007).
2. De Clercq, E. Emerging anti-HIV drugs. Expert Opin. Emerg. Drugs 2005, 10, 241-274.
3. De Clercq, E. Anti-HIV chemotherapy: current state of the art. Med. Chem. Res. 2004, 13, 439-478.
4. Jiang, S.; Lin, K.; Strick, N.; Neurath, A. R. Inhibition of HIV-1 infection by a fusion domain binding peptide from the HIV-1 envelope glycoprotein GP41. Biochem. Biophys. Res. Commun. 1993, 195, 533-538.
5. Kadow, J.; Wang, H. G.; Lin, P. F. Small-molecule HIV-1 gp120 inhibitors to prevent HIV-1 entry: an emerging opportunity for drug development. Curr. Opin. Invest. Drugs 2006, 7, 721-726.
6. Berger, E. A.; Murphy, P. M.; Farber, J. M. Chemokine receptors as HIV-1 coreceptors: Roles in viral entry, tropism, and disease. Annu. Rev. Immunol. 1999, 17, 657-700.
7. De Clercq, E. New antiviral agents in preclinical or clinical development. Adv. Antiviral Drug Des. 2004, 4, 1-62.
8. De Clercq, E. New Anti-HIV Agents and Targets. Med. Res. Rev. 2002, 22, 531-565.
9. Bean, P. New Drugs Targets for HIV. Clin. Infect. Dis. 2005, 41, 96-100.
10. Markovic, I.; Clouse, K. A. Recent advances in understanding the molecular mechanisms of HIV-1 entry and fusion: revisiting current targets and considering new options for therapeutic intervention. Curr. HIV Res. 2004, 2, 223-234.
11. Kazmierski, W. M.; Peckman, J. P.; Duan, M.; Kenakin, T. P.; Jenkinson, S.; Gudmundsson, K. S.; Piscitelli, S. C.; Feldman, P. L. Recent Progress in the Discovery of New CCR5 and CXCR4 Chemokine Receptor Antagonists as Inhibitors of HIV-1 Entry. Part 2. Curr. Med. Chem.-Anti-Infect. Agents 2005, 4, 133-152.
12. Afantitis, A.; Melagraki, G.; Sarimveis, H.; Koutentis, P. A.; Markopoulos, J.; Igglessi-Markopoulou, O. Investigation of substituent effect of 1-(3,3-diphenylpropyl)-piperidinyl phenylacetamides on CCR5 binding affinity using QSAR and virtual screening techniques. J. Comput.-Aided Mol. Des. 2006, 20, 83-95.
13. Aher, Y. D.; Agrawal, A.; Bharatam, P. V.; Garg, P. 3D-QSAR studies of substituted l-(3, 3-diphenylpropyl)-piperidinyl amides and ureas as CCR5 receptor antagonists. J. Mol. Model. 2007, 13, 519-529.
14. Kellenberger, E.; Springael, J.-Y.; Parmentier, M.; Hachet-Haas, M.; Galzi, J.-L.; Rognan, D. Identification of Nonpeptide CCR5 Receptor Agonists by Structure-based Virtual Screening. J. Med. Chem. 2007, 50, 1294-1303.
15. Palczewski, K.; Kumasaka, T.; Hori, T.; Behnke, C. A.; Motoshima, H.; Fox, B. A.; Le Trong, I.; Teller, D. C.; Okada, T.; Stenkamp, R. E.; Yamamoto, M.; Miyano, M. Crystal structure of rhodopsin: A G protein-coupled receptor. Science 2000, 259, 739-745.
16. Vaidehi, N.; Floriano, W. B.; Trabanino, R.; Hall, S. E.; Freddolino, P.; Choi, E. J.; Zamanakos, G.; A. Goddard, W., III. Prediction of structure and function of G protein-coupled receptors. Proc. Natl. Acad. Sci., U.S.A. 2002, 99, 12622-12627.
17. Pierson, T. C.; Doms, R. W. HIV-1 entry inhibitors: new targets, novel therapies. Immunol. Lett. 2003, 85, 113-118.
18. Kazmiersky, W.; Bifulco, N.; Yang, H.; Boone, L.; DeAnda, F.; Watson, C.; Kenakin, T. Recent progress in discovery of small-molecule CCR5 chemokine receptor ligand as HIV-1 inhibitors. Bioorg. Med. Chem. 2003, 11, 2663-2676.
19. Kilby, J. M.; Eron, J. J. Novel therapies based on mechanisms of HIV-1 cell entry. N. Engl. J. Med. 2003, 348, 2228-2238.
20. Starr-Spirres, L. D.; Collman, R. G. HIV-1 entry and entry inhibitors as therapeutic agents. Clin. Lab. Med. 2002, 22, 681-701.
21. De Clercq, E. The bicyclam AMD3100 story. Nat. Rev. Drug. Discovery 2003, 2, 581-587.
22. Tusnády, G. E.; Simon, I. Principles Governing Amino Acid Composition of Integral Membrane. Proteins: Application to Topology Prediction. J. Mol. Biol. 1998, 283, 489-506.
23. Krogh, A.; Larsson, B.; von Heijne, G.; Sonnhammer, E. L. Predicting Transmembrane Protein Topology with a Hidden Markov Model: Application to Complete Genomes. J. Mol. Biol. 2001, 305, 567-580.
24. Jones, D. T.; Taylor, R.; Thornton, J. M. A Model Recognition Approach to the Prediction of All-Helical Membrane Protein Structure and Topology. Biochemistry 1994, 33, 3038-3049.
25. Gerlach, L. O.; Skerlj, R. T.; Bridger, G. J.; Schwartz, T. W. Molecular Interaction of Cyclam and Bicyclam Non-peptide Antagonists with the CXCR4 Chemokine Receptor. J. Biol. Chem. 2001, 276, 14154-14160.
26. Paterlini, M. G. Structure Modeling of the Chemokine Receptor CCR5: Implications for Ligand Binding and Selectivity. Biophys. J. 2002, 83, 3012-3031.
27. Sali, A.; Blundell, T. L. Comparative protein modelling by satisfaction of spatial restrains. J. Mol. Biol. 1993, 234, 779-815.
28. MOE (Molecular Operating Environment), 2006.08 Release; Chemical Computing Group, Inc.: Montreal, Canada, 2004.
29. Im, D.-S. Orphan G Protein-Coupled Receptors and Beyond. Jpn. J. Pharmacol. 2002, 90, 101-106.
30. Fiser, A.; Sali, A. Modeling of loops in protein structures. Protein Sci. 2000, 9, 1753-1773.
31. Bruccoleri, R. E. Application of Systematic Conformational Search to Protein Modeling. Mol. Simul. 1993, 10, 151-174.
32. Bruccolieri, R. E.; Karplus, M. Chain closure with bond angle variations. Macromolocules 1985, 18, 2767-2773.
33. Bruccolieri, R. E.; Karplus, M. Prediction of the Folding of Short Polypeptide Segments by Uniform Conformatinal Sampling. Biopolymers 1987, 26, 137-168.
34. Brooks, B. R.; Bruccolieri, R. E.; Olafson, B. D.; States, D. J.; Swamminathan, S.; Karplus, M. CHARMM: A Program for Macro-molecular Energy, Minimization, and Dynamics Calculations. J. Comput. Chem. 1983, 4, 187-217.
35. Li, H.; Tejero, R.; Monleon, D.; Bassolino-Klimas, D.; Abate-Shen, C.; Bruccolieri, R. E.; Montelione, G. T.; Homology modeling using simulated annealing of restrained molecular dynamics and conformational search with CONGEN: aplication in predicting the three-dimensional structure of murine homeodomain Msx-1. Protein Sci. 1997, 6, 956-970.
36. Bruccolieri, R. E.; Haber, E.; Novotny, J. Structure of antibody hypervariable loops reproduced by conformational search algorithm. Nature 1988, 335, 564-568.
37. Laskowski, R. A.; McArthur, M. W.; Moss, D. S.; Thornton, J. M. PROCHECK: a program to check the stereochemical quality of protein structures, J. Appl. Crystallogr. 1993, 26, 283-291.
38. Huang, X.; Shen, J.; Cui, M.; Shen, L.; Luo, X.; Ling, K.; Pei, G.; Jiang, H.; Chen, K. Molecular Dynamics Simulations on SDF-1α: Binding with CXCR4 Receptor. Biophys. J. 2003, 84, 171-184.
39. Cornell, W. D.; Cieplack, P.; Bayly, C. I.; Gould, I. R.; Merz, K. M.; Ferguson, Jr.; Spellmeyer, D. C.; Fox, T.; Caldwell, J. W.; Kollman, P. A. A second generation force field for the simulation of proteins, nucleic acids and organic molecules. J. Am. Chem. Soc. 1995, 117, 5179-5197.
40. Morris, G. M.; Goodsell, D. S.; Halliday, R. S.; Hart, W.; Belew, R. K.; Olson, A. J. Automated Docking Using a Lamarckian Genetic Algorithm and Empirical Binding Free Energy Function. J. Comput. Chem. 1998, 19, 1639-1662.
41. Verdonk, M. L.; Cole, J. C.; Hartshorn, M. J.; Murray, C. W.; Taylor, R. D. Improved Protein-Ligand Docking Using GOLD. Proteins: Struct., Funct., Genet 2003, 52, 609-623.
42. Gasteiger, J.; Marsili, M. Iterative Partial Equalization of Orbital Electronegativity - A Rapid Access To Atomic Charges. Tetrahedron 1980, 36, 3219-3228.
43. Zhang, W. B.; Navenot, J. M.; Haribabu, B.; Tamamura, H.; Hiramatu, K.; Omagari, A.; Pei, G.; Manfredi, J. P.; Fujii, N.; Broach, J. R.; Peiper, S. C. A. Point Mutation That Confers Constitutive Activity to CXCR4 Reveals That T140 Is an Inverse Agonist and That AMD3100 and ALX40-4C Are Weak Partial Agonists. J. Biol. Chem. 2002, 277, 24515-24521.
44. Brelot, A.; Heveker, N.; Montes, M.; Alizon, M. Identification of Residues of CXCR4 Critical for Human Immunodeficiency Virus Coreceptor and Chemokine Receptor Activities. J. Biol. Chem. 2000, 275, 23736-23744.
45. Donzella, G. A.; Schols, D.; Lin, S. W.; Este, J. A.; Nagashima, K. A.; Maddon, P. J.; Allaway, G. P.; Sakmar, T. P.; Henson, G.; De Clercq, E.; Moore, J. P. AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. Nat. Med. 1998, 4, 72-77.
46. Hatse, S.; Princen, K.; Gerlach, L. O.; Bridger, G.; Henson, G.; Clercq, E.; Schwartz T. W.; Schols, D. Mutation of Asp171 and Asp262 of the chemokine receptor CXCR4 impairs its coreceptor function for human immunodeficiency virus-1 entry and abrogates the antagonistic activity of AMD3100. Mol. Pharmacol. 2001, 60, 164-173.
47. Hatse, S.; Princen, K.; Vermeire, K.; Gerlach, L.-O.; Rosenkilde, M. M.; Schwartz, T. W.; Bridger, G.; De Clercq, E.; Schols, D.; Mutations at the CXCR4 interaction sites for AMD3100 influence anti-CXCR4 antibody binding and HIV-I entry. FEBS ett. 2003, 546, 300-306.
48. Ho, S. N.; Hunt, H. D.; Horton, R. M.; Pullen, J. K.; Pease, L. R. Site-directed mutagenesis by overlap extension using polymerase chain reaction. Gene 1989, 77, 51-59.
49. Rosenkilde, M. M.; Gerlach, L. O.; Jacobsen, J. S.; Skerlj, R. T.; Bridger, G. J.; Schwartz, T. W. Molecular Mechanism of AMD3100 Antagonism in the CXCR4 Receptor. J. Biol. Chem. 2004, 279, 3033-3041.
50. Seibert, C.; Ying, W.; Gavrilov, S.; Tsamis, F.; Kuhmann, S. E.; Palani, A.; Tagat, J. R.; Clader, J. W.; McCombie, S. W.; Baroudy, B. M.; Smith, S. O.; Dragic, T.; Moore, J. P.; Sakmar, T. P.; Interaction of small molecule inhibitors of HIV-1 entry with CCR5. Virology 2006, 349, 41-54.
51. Zhou, N.; Luo, Z.; Hall, J. W.; Luo, J.; Han, X.; Huang, Z.; Molecular modeling and site-directed mutagenesis of CCR5 reveal residues critical for chemokine binding and signal transduction. Eur. J. Immunol. 2000, 30, 164-173.
52. Dragic, T.; Trkola, A.; Thompson, D. A.; Cormier, E. G.; Kajumo, F. A.; Maxwell, E.; Lin, S. W.; Ying, W.; Smith, S. O.; Sakmar, T. P.; Moore, J. P. A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5. Proc. Natl. Acad. Sci., U.S.A. 2000, 97, 5639-5644.
53. Baba, M.; Nishimura, O.; Kanzaki, N.; Okamoto, M.; Sawada, H.; Iizawa, Y.; et al. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc. Natl. Acad. Sci., U.S.A. 1999, 96, 5698-5703.
54. Bridger, G.; Skerlj, R.; Kaller, A.; Harwing, C.; Bogucki, D.; Wilson, T. R.; Crawford, J.; McEachern, E. J.; Atsma, B.; Nan, S.; Zhou, Y. World Patent WO 0022600, 2002.
55. Bridger, G.; Skerlj, R.; Kaller, A.; Harwing, C.; Bogucki, D.; Wilson, T. R.; Crawford, J.; McEachem, E. J.; Atsma, B.; Nan, S.; Zhou, Y. World Patent WO 0022599, 2002.
56. Bridger, G.; Skerlj, R.; Kaller, A.; Harwing, C.; Bogucki, D.; Wilson, T. R.; Crawford, J.; McEachem, E. J.; Atsma, B.; Nan, S.; Zhou, Y. World Patent WO 00234745, 2002.
57. Bridger, G.; Skerlj, R.; Kaller, A.; Harwing, C.; Bogucki, D.; Wilson, T. R.; Crawford, J.; McEachem, E. J.; Atsma, B.; Nan, S.; Zhou, Y. World Patent WO 055876, 2003.
58. Bridger, G.; Skerlj, R.; Kalter, A.; Harwig, C.; Bogucki, D.; Wilson, T. R.; Crawford, J.; McEachem, E. J.; Atsma, B.; Nan, S.; Zhou, Y.; Schools, D.; Smith, C. D.; Di Fluir, R, M. U.S. Patent 7091217, 2004.
59. Ichiyama, K.; Yokohama-Kumakura, S.; Tanaka, Y.; Tanaka, R.; Hirose, K.; Bannai, K.; Edamatsu, T.; Yanaka, M.; Niitani, Y.; Miyako-Kurosaki, N.; Takaku, H.; Koyanagi, Y.; Yamamoto, N. A duodenally absorbable CXC chemokine receptor 4 antagonist, KRH-1636, exhibits a potent and selective anti-HIV-1 activity. Proc. Natl. Acad. Sci., U.S.A. 2003, 100, 4185-4190.
60. Murakami, T.; Yoshida, A.; Tanaka, R.; Mitsubishi, S.; Hirose, K.; Yanaka, M.; Yamamato, N.; Tanaka, Y. KRH-2731: An Orally Bioavailable CXCR4 Antagonist Is a Potent Inhibitor of HTV-1 Infection. In 2004 Antivirals Pipeline Report; Camp, R., Ed.; Proceedings of the 11th Conference on Retroviruses and Opportunistic Infection, San Francisco CA, Feb. 8-11, 2004; Treatment Action Group: San Francisco, CA, 2004; Abstract No. 541.
61. Yamazaki, T.; Saitou, A.; Ono, M.; Yokohama, S.; Bannai, K.; Hiroswe, K.; Yanaka, M. World Patent WO 029218, 2003.
62. Yamazaki, T.; Kikumoto, S.; Ono, M.; Saitou, A.; Takahashi, H.; Kumakura, S.; Hirose, K. World Patent WO 024697, 2004.
63. Bridger, G. J.; Skerlj, R. T.; Padmanabhan, S.; Martellucci, S. A.; Henson, G. W.; Struyf, S.; Witvrouw, M.; Schols, D.; De Clercq, E. Synthesis and Structure-Activity Relationships of Phenylenebis(methylene)-Linked Bis-azamacrocycles That Inhibit HIV-1 and HTV-2 Replication by Antagonism of the Chemokine Receptor CXCR4. J. Med. Chem. 1999, 42, 3971-3981.
64. De Clercq, E. Inhibition of HIV Infection by Bicyclams, Highly Potent and Specific CXCR4 Antagonists. Mol. Pharmacol. 2000, 57, 833-839.
65. Esté, J. A.; Cabrera, C.; De Clercq, E.; Struyf, S.; Van Damme, J.; Bridger, G.; Skerlj, R. T.; Abrams, M. J.; Henson, G.; Gutierrez, A.; Clotet, B.; Schols, D. Activity of Different Bicyclam Derivatives against Human Immunodeficiency Virus Depends on Their Interaction with the CXCR4 Chemokine Receptor. Mol. Pharmacol. 1999, 55, 67-73.
66. Egberink, H. F.; De Clercq, E.; Van Vliet, A. L. W.; Balzarini, J.; Bridger, G. J.; Henson, G.; Horzinek, M. C.; Schols, D. Bicyclams, selective antagonists of the human chemokine receptor CXCR4, potently inhibit feline immunodeficiency virus replication. J. Virol. 1999, 73, 6346-6352.
67. Hatse, S.; Princen, K.; De Clercq, E.; Rosenkilde, M. M.; Schwartzb, T. W.; Hernandez-Abad, P. E.; Skerlj, R. T.; Bridger, G. J.; Schols, D. AMD3465, a monomacrocyclic CXCR4 antagonist and potent HIV entry inhibitor. Biochem. Pharmacol. 2005, 70, 752-761.
68. Princen, K.; Hatse, S.; Vermeire, K.; Aquaro, S.; De Clercq, E.; Gerlach, L.-O.; Rosenkilde, M.; Schwartz, T. W.; Skerlj, R.; Bridger, G.; Schols, D. Inhibition of Human Immunodeficiency Virus Replication by a Dual CCR5/CXCR4 Antagonist. J. Virol. 2004, 78, 12996-13006.
69. Tamamura, H.; Araki, T.; Ueda, S.; Wang, Z.; Oishi, S.; Esaka, A.; Trent, J. O.; Nakashima, H.; Yamamoto, N.; Peiper, S. C.; Otaka, A.; Fujii, N. Identification of novel low molecular weight CXCR4 antagonists by structural tuning of cyclic tetrapeptide scaffolds. J. Med. Chem. 2005, 48, 3280-3289.
70. Rosenkilde, M. M.; Gerlach, L. O.; Hatse, S.; Skerlj, R. L.; Schols, D.; Bridger, G.; Schwartz, T. W. Molecular mechanism of action of monociclam versus biciclam non-peptide antagonist in the CXCR4 chemokine receptor. J. Biol. Chem. 2007, 282, 27354-27365.
71. Palani, A.; Shapiro, S.; Clades, J. W.; Greenlee, W. J.; Blythin, D.; Cox, K.; Wagner, N. E.; Strizki, J.; Baroudy, B. M.; Dan, N. Biological evaluation and interconversion studies of rotamers of SCH 351125, an orally bioavailable CCR5 antagonist. Bioorg. Med. Chem. Lett. 2003, 13, 705-708.
72. Tsamis, F.; Gavrilov, S.; Kajumo, F.; Seibert, C.; Kuhmann, S.; Ketas, T.; Trkola, A.; Palani, A.; Clader, J. W.; Tagat, J. R.; McCombie, S.; Baroudy, B.; Moore, J. P.; Sakmar, T. P.; Dragic, T. Analysis of the Mechanism by Which the Small-Molecule CCR5 Antagonists SCH-351125 and SCH-350581 Inhibit Human Immunodeficiency Virus Type 1 Entry. J. Virol. 2003, 77, 5201-5208.
73. Billick, E.; Seibert, C.; Pugach, P.; Ketas, T.; Trkola, A.; Endres, M. J.; Murgolo, N. J.; Coates, E.; Reyes, G. R.; Baroudy, B. M.; Sakmar, T. P.; Moore, J. P.; Kuhmann, S. E. The Differential Sensitivity of Human and Rhesus Macaque CCR5 to Small-Molecule Inhibitors of Human Immunodeficiency Virus Type 1 Entry Is Explained by a Single Amino Acid Difference and Suggests a Mechanism of Action for These Inhibitors. J. Virol. 2004, 78, 4134-4144.
74. Maeda, K.; Yoshimura, K.; Shibayama, S.; Habashita, H.; Tada, H.; Sagawa, K.; Mikayawa, T.; Auki, M.; Fukushima, D.; Mitsuya, H. Novel Low Molecular Weight Spirodiketopiperazine Derivatives Potently Inhibit R5 HIV-1 Infection through Their Antagonistic Effects on CCR5. J. Biol. Chem. 2001, 276, 35194-35200.
75. Shibayama, S.; Sagawa, K.; Watanabe, N.; Takeda, K.; Tada, H.; Fukushima, D. World Patent WO 2004054616, 2004.
76. Takaoka, Y.; Okamoto, M.; Genba, Y. World Patent WO 2004026874, 2004.
77. Takaoka, Y.; Nishizawa, R.; Shibayama, S.; Sagawa, K.; Matsuo, M. Y. World Patent WO 2002074770, 2002.
78. Imawaka, H.; Shibayama, S.; Takaoka, Y. World Patent WO 2003035074, 2003.
79. Cumming, J.; Tucker, H. World Patent WO 2003042177, 2003.
80. Cumming, J. World Patent WO 2003042178, 2003.
81. Cumming, J. World Patent WO 2003080574, 2003.
82. Cumming, J.; Winter, J. World Patent WO 2004018425, 2004.
83. Burrows, J.; Cumming, J. World Patent WO 2002076, 2002.
84. Willouhby, C. W.; Rosauer, K. G.; Hale, J. J.; Budhu, R. J.; Mills, S. G.; Chapman, K. T.; MacCoss, M.; Malkowitz, L.; Springer, M. S.; Gould, S. L.; DeMartino, J. A.; Siciliano, S. J.; Cascieri, M. A.; Carella, A.; Catver, G.; Colmes, K.; Schlief, W. A.; Danzeisen, R.; Hazuda, D.; Kessler, J.; Lineberger, J.; Miller, M.; Emini, E. A. 1,3,4 Trisubstituted pyrrolidine CCR5 receptor antagonists bearing 4-aminoheterocycle substituted piperidine side chains. Bioorg. Med. Chem. Lett. 2003, 13, 427-431.
85. Kazmierski, W. M.; Aquino, C. J.; Bifulco, N.; Boros, E. E.; Chauder, B. A.; Chong, P. Y.; Duan, M.; Deanada, F., Jr.; Koble, C. S.; Malean, E. W.; Peckham, J. P.; Perkins, A. C.; Thompson, J. B.; Vanderwall, D. World Patent WO 2004054974, 2004.
86. Duan, M., Kazmierski, W. M.; Aquino, C. J. World Patent WO 200405481, 2004.
87. Peckham, J. P.; Aquino, C. J.; Kazmierski, W. M. World Patent WO 2004055010, 2004.
88. Aquino, C. J.; Chong, P. Y.; Duan, M.; Kazmierski, W. M. World Patent WO 2004055011, 2004.
89. Youngman, M.; Kazmierski, W. M.; Yang, H.; Aquino, C. J. World Patent WO 2004055012, 2004.
90. Yang, H.; Kazmierski, W. M.; Aquino, C. J. World Patent WO 2004055016, 2004.
91. Aramaki, Y.; Seto, M.; Okawa, T.; Oda, T.; Kanzaki, N.; Shiraishi, M. Synthesis of 1-benzothiepine and 1-benzazepine derivatives as orally active CCR5 antagonists. Chem. Pharm. Bull. 2004, 52, 254-258.
92. Seto, M.; Aramaki, Y.; Okawa.; T.; Miyamoto, N.; Aikawa, K.; Kanzaki, N.; Shiraishi, M. Orally active antagonists as Anti-HIV-1 Agents: Synthesis and Biological Activity of 1-Benzothiepine 1,1Dioxide and 1-Benzazepine derivatives containing a tertiary Amine Moiety. Chem. Pharm. Bull. 2004, 52, 577-590.
93. Perros, M.; Price, D. A.; Stammen, B. L. C.; Wood, A. World Patent WO 2003084954, 2003.
94. Basford, P. A.; Stephenson, P. T.; Taylor, S. C. J.; Wood, A. World Patent WO 2003084954, 2003.
95. Armour, D. R.; Price, D. A.; Stammen, B. L. C.; Wood, A.; Perros, M.; Edwards, M. P. World Patent WO 2000038680, 2000.
96. Rusconi, S.; Scozzafava, A.; Mastrolorenzo, A.; Supuran, T. C. New Advances in HIV Entry Inhibitors Development. Curr. Drug Targets Infect. Disord. 2004, 4, 339-355.
97. Irnamura, S.; Kurasawa, O.; Nara, Y.; Ichikawa, T.; Nishikawa, Y.; Iida, T.; Hashiguchi, S.; Kanzaki, N.; Lizawa, Y.; Baba, M.; Sugihara, Y. CCR5 antagonists as anti-HIV-1 agents. Part 2: Synthesis and biological evaluation of N-[3-(4-benzylpiperidin-1-yl)propyl]-N,N′-diphenylureas. Bioorg. Med. Chem. 2004, 12, 2295-2306.
98. Irnamura, S.; Ishihara, Y.; Hattori, T.; Kurasawa, O.; Matsushita, Y.; Sugihara, Y.; Kanzaki, N.; Lizawa, Y.; Baba, M.; Hashiguchi, S. CCR5 antagonists as Anti-HIV-1 agents. 1. Synthesis and Biological Evaluation of 5-oxopyrrolidine-3-carboxamide Derivatives. Chem. Pharm. Bull. 2004, 52, 63-73.
99. Debnath, A. K. Generation of Predictive Pharmacophore Models for CCR5 Antagonists: Study with Piperidine- and Piperazine-Based Compounds as a New Class of HIV-1 Entry Inhibitors. J. Med Chem. 2003, 46, 4501-4515.
100. Verdonk, M. L.; Cole, J. C.; Hartshorn, M. J.; Murray, C. W.; Taylor, R. D. Virtual screening using protein-ligand docking: avoiding artificial enrichment. J. Chem. Inf. Comput. Sci. 2004, 44, 793-806.
101. Maybride Bringing life to drug discovery, Maybridge Databases Autumn 2005; Fisher Scientific International: England, 2005.
102. Labute, P. Flexible Alignment of Small Molecules. Chemical Computing Group, Inc.: Montreal, Canada, 2004. (Available via the Internet at http://www.chemcomp.com/journal/malign.htm, accessed Dec. 23, 2007.)
103. McGann, M. R.; Almond, H. R.; Nicholls, A.; Grant, J. A.; Brown, F. K. Gaussian docking functions. Biopolymers 2003, 68, 76-90.
104. Ritchie, D. W.; Kemp, G. J. L. Fast computation, rotation, and comparison of low resolution spherical harmonic molecular surfaces. J. Comput. Chem. 1999, 20, 383-395.
105. Ritchie, D. W.; Kemp, G. J. L.; Protein docking using spherical polar Fourier correlations. Proteins: Struct., Funct., Genet. 2000, 39, 178-194.
106. Wang, R.; Wang, S. How does consensus scoring work for virtual library screening? An idealized computer experiment. J. Chem. Inf. Comput. Sci. 2001, 41, 1422-1426.
107. Lin, J.; Clark, T. An analytical, variable resolution, complete description of static molecules and their intermolecular binding properties. J. Chem. Inf. Model. 2005, 45, 1010-1016.
108. Grant, A. J.; Pickup, B. T. A fast method of molecular shape comparison: a simple application of a Gaussian description of molecular shape. J. Comput. Chem. 1996, 17, 1653-1659.
109. OMEGA, version 2.1.0; OpenEye Scientific Software, Inc.: Santa Fe, NM., 2006.
110. Warren, G. L.; Andrews, C. V.; Capelli, A.; Clarke, B.; LaLonde, J.; Lambert, M. H.; Lindvall, M.; Nevins, N.; Sernus, S. F.; Senger, S.; Tedesco, G.; Wall, I. D.; Woolven, J. M.; Peishoff, C. E.; Head, M. S. A critical assessment of docking programs and scoring functions. J. Med. Chem. 2006, 49, 5912-5931.
111. Liang, X.; Parkinson, J. A.; Weisblupl, M.; Gould, R. O.; Paisey, S. J.; Park, H.; Hunter, T. M.; Blindauer, C. A.; Parsons, S.; Sadler, P. J. Structure and Dynamics of Metallomacrocycles: Recognition of Zinc Xylyl-Bicyclam by an HIV Coreceptor. J. Am. Chem. Soc. 2002, 124, 9105-9112.
112. Trent, J. O.; Wang, Z. X.; Murray, J. L.; Shao, W.; Tamamura, H.; Fujii, N.; Peiper, S. G Lipid Bilayer Simulations of CXCR4 with Inverse Agonist and Weak Partial Agonist. J. Biol. Chem. 2003, 278, 47136-47144.
113. McDonald, I. K.; Thornton, J. M. Satisfying Hydrogen Bonding Potential in Proteins. J. Mol. Biol. 1994, 238, 777-793.
114. Dragic, T.; Trkola, A.; Lin, S. W.; Nagashima, K. A.; Kajumo, F.; Zhao, L.; Olson, W. C.; Wu, L.; Mackay, C. R.; Allaway, G. P.; Sakmar, T. P.; Moore, J. P.; Maddon, P. J. Amino-terminal substitutions in the CCR5 co-receptor impair gpl20 binding and human immunodeficiency virus type 1 entry. J. Virol. 1998, 72, 279-285.
115. Rucker, J.; Samson, M.; Doranz, B. J.; Libert, F.; Berson, J. F.; Yi, Y.; Smyth, R. J.; Collman, R. G.; Broder, C.C.; Vassart, G.; Doms, R. W.; Parmentier, M. Regions in beta-chemokine receptors CCR5 and CCR2b that determine HIV-1 cofactor specificity. Cell 1996, 87, 437-446.
116. Fano, A.; Ritchie, D. W.; Carrieri, A. Modelling the structural basis of human CCR5 chemokine receptor function: from homology model-building and molecular dynamics validation to agonist and antagonist docking. J. Chem. Inf. Model. 2006, 46, 1223-1235.
117. Kontoyianni, M.; McClellan, L. M.; Sokol, G. S. Evaluation of Docking Performance: Comparative Data on Docking Algorithms. J. Med. Chem. 2004, 47, 558-565.
118. Bissantz, C.; Folkers, C.; Rognan, D. Protein-based virtual screening of chemical databases. 1. Evaluation of different docking/scoring combinations. J. Med. Chem. 2000, 43, 4759-4767.
119. Gutiérrez-de-Terán, H.; Pastor, M.; Centeno, N. B.; Aqvist, J.; Sanz, F. Comparative analysis of putative agonist binding modes in the human Al adenosine receptor. ChemBioChem 2004, 5, 841-849.
120. Shields, G. C.; Laughton, C. A.; Orozco, M. Molecular dynamics simulations of the d(T·A·T) triple helix. J. Am. Chem. Soc. 1997, 119, 7463-7469.
121. Bvers, A.; Hessler, G.; Matter, H.; Klabunde, T. Virtual Screening of Biogenic Amine-Binding G-Protein Coupled Receptors: Comparative Evaluation of Protein- and Ligand-Based Virtual Screening Protocols. J. Med. Chem. 2005, 48, 5448-5465.
122. Rabal, O.; Schneider, G.; Borrell, J. I.; Teixidó, J. Structure-Based Virtual Screening of FGFR Inhibitors. Cross-Decoys and Induced-Fit Effect. BioDrugs 2007, 21, 31-45.
123. Teixidó, J.; Borrell, J. I.; Nonell, S.; Batllori, X.; Pettersson, S.; Ros, L.; Puig de la Bellacasa, R.; Rabal, M. O.; Pérez-Nueno, V.; Esté, J.; Clotet, I.; Armand-Ugón, M.; Nuevos sistemas polinitrogenados como agentes anti-VIH. Spanish Patent ES200602764, Oct. 26, 2006.
124. Pettersson, S.; Clotet-Codina, I.; Esté, J. A.; Borrell, J. I.; Teixidó, J. Recent advances in combinatorial chemistry applied to development of anti-HIV drugs. Mini Rev. Med. Chem. 2006, 6, 91-108.
125. Hawkins, P. D. C.; Skillman, G. A.; Nicholls, A. Comparison of Shape Matching and Docking as Virtual Screening Tools. J. Med. Chem. 2007, 50, 74-82.
126. Castonguay, L. A.; Weng, Y.; Adolfsen, W.; Di Salvo, J.; Kilburn, R.; Caldwell, C. G.; Daugherty, B. L.; Finke, P. E.; Hale, J. J.; Lynch, C. L.; Mills, S. G.; MacCoss, M.; Springer, M. S.; DeMartino, J. A. Binding of 2-Aryl-4-(piperidin-1-yl)butanamines and 1,3,4-Trisubstituted Pyrrolidines to Human CCR5: A Molecular Modeling Guided Mutagenesis Study of the Binding Pocket. Biochemistry 2003, 42, 1544-1550.