Simple but highly effective three-dimensional chemical-feature-based pharmacophore model for diketo acid derivatives as hepatitis C virus RNA-dependent RNA polymerase inhibitors

Journal of Medicinal Chemistry

Volumn 48, Issue 20, 2005, Pages 6304-6314

  Di Santo, Roberto ^a   Fermeglia, Maurizio ^b   Ferrone, Marco ^b   Paneni, Maria Silvia ^b   Costi, Roberta ^a   Artico, Marino ^a   Roux, Alessandra ^a   Gabriele, Mirko ^a   Tardif, Keith D ^c   Siddiqui, Aleem ^d   Pricl, Sabrina ^b  

^a SAPIENZA UNIVERSITY OF ROME   (Italy)

^b UNIVERSITY OF TRIESTE   (Italy)

^c UNIVERSITY OF COLORADO   (United States)

^d UNIVERSITY OF CALIFORNIA SAN DIEGO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,4 DIOXO 5 HEXANOIC ACID; DIKETO ACID DERIVATIVE; ENZYME INHIBITOR; HEXANOIC ACID DERIVATIVE; INTEGRASE INHIBITOR; RNA DIRECTED RNA POLYMERASE INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; COMPUTER PROGRAM; CORRELATION COEFFICIENT; DRUG STRUCTURE; DRUG SYNTHESIS; HEPATITIS C VIRUS; HYDROGEN BOND; IC 50; MOLECULAR MODEL; NONHUMAN; PHARMACOPHORE; STATISTICAL SIGNIFICANCE; STRUCTURE ANALYSIS; THREE DIMENSIONAL IMAGING;

ANTIVIRAL AGENTS; DRUG DESIGN; ENZYME INHIBITORS; HEPACIVIRUS; KETO ACIDS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP; RNA REPLICASE;

EID: 26444491094     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0504454     Document Type: Article

References (49)

1. Choo, Q. L.; Kuo, G.; Weiner, A. J.; Overby, L. R.; Bradley, D. W.; Houghton, M. Isolation of a cDNA Clone Derived from a Blood-Borne non-A non-B Viral Hepatitis Genome. Science 1989, 244, 359-362.
2. Alter, M. J.; Kruszon-Moran, D.; Nainan, O. V.; McQuillan, G. M.; Gao, F.; Moyer, L. A.; Kaslow, R. A.; Margolis, H. S. The Prevalence of Hepatitis C Virus Infection in the United States, 1988 through 1994. N. Engl. J. Med. 1999, 341, 556-562.
3. Leyssen, P.; De Clercq, E.; Neyts, J. Perspectives for the Treatment of Infections with Flaviviridae. Clin. Microbiol. Rev. 2000, 13, 67-82.
4. Memon, M. I.; Memon, M. A. Hepatitis C: an epidemiological review. J. Viral Hepatitis 2000, 9, 84-100.
5. Liang, T. J.; Rehermann, B.; Seeff, L. B.; Hoofnagle, J. H. Pathogenesis, Natural History, Treatment and Prevention of Hepatitis C. Ann. Intern. Med. 2000, 132, 296-305.
6. Lauer, G. M.; Walker, B. D. Hepatitis C Virus Infection. N. Engl. J. Med. 2001, 345, 41-52.
7. (a) Di Bisceglie, A. M.; Hoofnagle, J. H. Optimal Therapy of Hepatitis C. Hepatology 2002, 36 (Suppl. 1), S121-127.
8. (b) Chandler, G.; Sulkowski, M. S.; Jenckes, M. W.; Torbenson, M. S.; Herlong, H. F.; Bass, E. B.; Gebo, K. A. Treatment of Chronic Hepatitis C: A Systematic Review. Hepatology 2002, 36, S135-144.
9. Scott, J. J.; Perry, C. M. Interferon-α-2b Plus Ribavirin. A Review of its Use in the Management of Chronic Hepatitis C. Drugs 2002, 62, 507-556.
10. Manns, M. P.; McHutchison, J. G.; Gordon, S. C.; Rustgi, V. K.; Shiffman, M.; Goodman, Z. D.; Koury, K.; Ling, M.; Albrecht, J. K. Peginterferon alfa-2b Plus Ribavirin Compared with Interferon alfa-2b Plus Ribavirin for Initial Treatment of Chronic Hepatitis C: a Randomised Trial. Lancet 2001, 358, 958-965.
11. Murphy, F. A.; Fauquet, C. M.; Bishop, D. H.; Ghabrial, S. A.; Jarvis, A. W.; Martelli, G. P.; Mayo, M. A.; Summers, M. D. Classification and Nomenclature of Viruses: Sixth Report of the International Committee on Taxonomy of Viruses; Springer-Verlag: Wien, Germany, 1995; pp 424-426.
12. Lindenbach, B. D.; Rice, C. M. Flaviviridae: the Viruses and their Replication. In Fields Virology, 4th ed.; Knipe, D. M., Howley, P. M., Griffin, D. E., Lamb, R. A., Martin, M. A., Riozman, B., Eds.; Lippincott, Wilkins and Wilkins: Philadephia, PA, 2001; pp 991-1041.
13. Behrens, S.-E.; Tomei, L.; De Francesco, R. Identification and Properties of the RNA-Dependent RNA Polymerase of Hepatitis C Virus. EMBO J. 1996, 15, 12-22.
14. Ago, H.; Adachi, T.; Yoshida, A.; Yamamoto, M.; Habuka, N.; Yatsunami, K.; Miyano, M. Crystal Structure of the RNA-Dependent RNA Polymerase of Hepatitis C Virus. Structure 1999, 7, 1417-1426.
15. Bressanelli, S.; Tomei, L.; Roussel, A.; Incitti, I.; Vitale, R. L.; Mathieu, M.; De Francesco, R.; Rey, F. A. Crystal Structure of the RNA-Dependent RNA Polymerase of Hepatitis C Virus. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 13034-13039.
16. Lesburg, C. A.; Cable, M. B.; Ferrari, E.; Hong, Z.; Mannarino, A. F.; Weber, P. C. Crystal Structure of the RNA-Dependent RNA Polymerase from Hepatitis C Virus Reveals a Fully Encircled Active Site. Nat. Struct. Biol. 1999, 6, 937-943.
17. Lohmann, V.; Roos, A.; Korner, F.; Koch, J. O.; Bartenschlager, R. Biochemical and Kinetic Analyses of NS5B RNA-Dependent RNA Polymerase of Hepatitis C Virus. Virology 1998, 249, 108-118.
18. Ishii, K.; Tanaka, Y.; Yap, C. C.; Aizaki, H.; Matsuura, Y.; Miyamura, T. Expression of Hepatitis C Virus NS5B Protein: Characterization of its RNA Polymerase Activity and RNA Binding. Hepatology 1999, 29, 1227-1235.
19. Johnson, R. B.; Sun, X. L.; Hockman, M. A.; Villarreal, E. C.; Wakulchik, M.; Wang, Q. M. Specificity and Mechanism Analysis of Hepatitis C Virus RNA-Dependent RNA Polymerase. Arch. Biochem. Biophys. 2000, 377, 129-134.
20. Ferrari, E.; Wrigtht-Minogue, J.; Fang, J. W.; Baroudy, B. M.; Lau, J. Y.; Hong, Z. Characterization of Soluble Hepatitic C Virus RNA-Dependent RNA Polymerase Expressed in Escherichia coli. J. Virol. 1999, 73, 1649-1654.
21. Rodriguez, P. L.; Carrasco, L. Gliotoxin: Inhibitor of Poliovirus RNA Synthesis that Blocks the Viral RNA Polymerase 3Dpol. J. Virol. 1992, 66, 1971-1976.
22. (a) Stuyver, L. J.; Whitaker, T.; McBrayer, T. R.; Hernandez-Santiago, B. I.; Lostia, S.; Tharnish, P. M.; Ramesh, M.; Chu, C. K.; Jordan, R.; Shi, J.; Rachakonda, S.; Watanabe, K. A.; Otto, M. J.; Schinazi, R. F. Ribonucleoside Analogue That Blocks Replicaton of Bovine Viral Diarrhea and Hepatitis C Viruses in Culture. Antimicrob. Agents Chemother. 2003, 47, 244-254.
23. (b) Carroll, S. S.; Tomassini, J. E.; Bosserman, M.; Getty, K.; Stahlhut, M. W.; Eldrup, A. B.; Baht, B.; Hall, D.; Simcoe, A. L.; LaFemina, R.; Rutkowski, C. A.; Wolanski, B.; Yang, Z.; Migliaccio, G.; DeFrancesco, R.; Kuo, L. C.; MacCoss, M.; Olsen, D. B. Inhibition of Hepatitis C Virus RNA Replication by 2′-Modified Nucloside Analogues. J. Biol. Chem. 2003, 278, 11979-11984.
24. Shim, J.; Larson, G.; Lai, G.; Naim, V.; Wu, S.; Canonical, J. Z. 3′-Deoxyribonucleotides as Chain Terminator for HCV NS5B RNA Polymerase. Antiviral Res. 2003, 243-251.
25. (a) Reddy, T. J.; Chan, L.; Turcotte, N.; Proulx, M.; Pereira, O. Z.; Das, S. K.; Siddiqui, A.; Wang, W.; Poisson, C.; Yannopoulos, C. G.; Bilimoria, D.; L'Heureux, L.; Alaoui, H. M. A.; Nguyen-Ba, N. Further, SAR Studies on Novel Small, Molecule Inhibitors of the Hepatitis C (HCV) NS5B Polymerase. Bioorg. Med. Chem. Lett. 2003, 13, 3341-3344.
26. (b) Wang, M.; Ng, K. K. S.; Cherney, M. M.; Chan, L.; Yannopoulos, C. G.; Bedard, J.; Morin, N.; Nguyen-Ba, N.; Alaoui-Ismaili, M. H.; Bethell, R. C.; James, M. N. G. Nonnucleoside Analogue Inhibitors Bind to Allosteric Site on HCV NS5B Polymerase. J. Biol. Chem. 2003, 278, 9489-9495.
27. (c) Dhanak, D.; Duffy, K. J.; Johnston, V. K.; Lin-Goerke, J.; Darcy, M.; Shaw, A. N.; Gu, B.; Silverman, C.; Gates, A. T.; Nonnemacher, M. R.; Earashaw, D. L.; Casper, D. J.; Kaura, A.; Baker, A.; Greenwood, C.; Gutshall, L. L.; Maley, D.; DelVecchio, A.; Macarron, R.; Hofmann, G. A.; Alnoah, Z.; Cheng, H.-Y.; Chan, G.; Khandekar S.; Keenan, R. M.; Sarisky, R. T. Identification and Biological Characterization of Heterocyclic Inhibitors of the Hepatitis C Virus RNA-Dependent RNA Polymerase. J. Biol. Chem. 2002, 277, 38322-38327.
28. (d) Chan, L.; Reddy, T. J.; Proulx, M.; Das, S. K; Pereira, O.; Wang, W.; Siddiqui, A.; Yannopoulos, C. G.; Poisson, C.; Turcotte, N.; Drouin, A.; Alaoui-Ismaili, M. H.; Bethell, R.; Hamel, M.; L'Heureux, L.; Bilimoria, D.; Nguyen-Ba, N. Identification of N,N-Disubstituted Phenylalanines as a Novel Class of Inhibitors of Hepatitis C NS5B Polymerase. J. Med. Chem. 2003, 46, 1283-1285.
29. (e) De Francesco, R.; Tomei, L.; Altamura, S.; Summa, V.; Migliaccio, G. Approaching a New Era for Hepatitis C Virus Therapy: Inhibitors of the NS3-4A Serine Protease and the NS5B RNA-Dependent RNA Polymerase. Antiviral Res. 2003, 58, 1-16.
30. (f) Summa, V.; Petrocchi, A.; Pace, P.; Matassa, V. G.; DeFrancesco, R.; Altamura, S.; Tomei, L.; Koch, U.; Neuner, P. Discovery of α,γ- Diketo Acids as Potent, Selective and Reversible Inhibitors of Hepatitis C Virus NS5B RNA Dependent RNA Polymerase. J. Med. Chem. 2004, 47, 14-17.
31. (g) Gu, B.; Johnston, V. K.; Gutshall, L. L.; Nguyen, T. T.; Gontarek, R. R.; Darcy, M. G.; Tedesco, R.; Dhanak, D.; Duffy, K. J.; Kao, C. C.; Sarisky, R. T. Arresting Initiation of Hepatitis C Virus RNA Synthesis Using Heterocyclic Derivatives. J. Biol. Chem. 2003, 278, 16602-16607.
32. (h) Love, R. A.; Parge, H. E.; Yu, X.; Hickey, M. J.; Diehl, W.; Gao, J.; Wriggers, H.; Ekker, A.; Wang, L.; Thomson, J. A.; Dragovich, P. S.; Furhman, S. A. J. Virol. 2003, 77, 7575-7581.
33. Altamura, S.; Tomei, L.; Koch, U.; Neuner, P. J.; Summa, V. Diketoacid-Derivatives as Inhibitors of Polymerases. PCT Int. Appl. WO 200006529, 2000; CAN 132: 132323, 2000.
34. Artico, M.; Di Santo, R.; Costi, R.; Novellino, E.; Greco, G.; Massa, S.; Tramontano, E.; Marongiu, M. E.; De Montis, A.; La Colla, P. Geometrically and Conformationally Restrained Cinnamoyl-Compounds as Inhibitors of HIV-1 Integrase: Synthesis, Biological Evaluation and Molecular Modeling. J. Med. Chem. 1988, 31, 3948-3960.
35. Di Santo, R.; Costi, R.; Artico, M.; Tramontano, E.; La Colla, P.; Pani A. HIV-1 Integrase Inhibitors that Block HIV-1 Replication in Infected Cells. Planning Synthetic Derivatives from Natural Products. Pure Appl. Chem. 2003, 75, 195-206.
36. Costi, R.; Di Santo, R.; Artico, M.; Massa, S.; Ragno, R.; Loddo, R.; La Colla, M.; Tramomtano, E.; La Colla, P.; Pani. A. 2,6-Bis-(3,4,5- trihydroxybenzylidene) derivatives of cyclohexanone: novel potent HIV-1 integrase inhibitors that prevent HIV-1 multiplication in cell-based assays. Bioorg. Med. Chem. 2004, 12, 199-215.
37. Costi, R.; Di Santo, R.; Artico, M.; Roux, A.; Ragno, R.; Massa, S.; Tramomtano, E.; La Colla, M.; Loddo, R.; Marongiu, M. E.; Pani, A.; La Colla, P. 6-Aryl-2,4-dioxo-5-hexenoic Acids, Novel Integrase Inhibitors Active Against HIV-1 Multiplication in Cell-Based Assays. Bioorg. Med. Chem. Lett. 2004, 14, 1745-1749.
38. Di Santo, R.; Costi, R.; Artico, M.; Ragno, R.; Greco, G.; Novellino, E.; Marchand, C.; Pommier, Y. Design, synthesis and biological evaluation of heteroaryl diketohexenoic and diketobutanoic acids as HIV-1 integrase inhibitors endowed with antiretroviral activity. Farmaco 2005, 60, 409-417.
39. Di Santo, R.; Costi, R.; Artico, M.; Marchand, C.; Pommier, Y. Quinoline inhibitors of retroviral integrase. U.S. Patent prov. num. US60/522,423, date of deposit March 10, 2004.
40. Sprague, P. Automated Chemical Hypothesis Generation and Database Searching with Catalyst. In Perspectives in Drug Discovery and Design; Anderson, P. S., Kenyon, G. L., Marshall, G. R., Muller, K., Eds.; ESCOM: Leiden, 1995; Vol. 3, pp 1-20.
41. Sutter, J.; Güner, O. F.; Hoffmann, R.; Li, H.; Waldman, M. In Pharmacophore, Perception Development and Use in Drug Design; Güner, O. F., Ed.; International University Line: La Jolla, CA, 2000; pp 504-506.
42. Smellie, A.; Teig, S. L.; Towbin, P. Poling: Promoting Conformational Variation. J. Comput. Chem. 1995, 16, 171-187.
43. Smellie, A.; Kahn, S. D.; Teig, S. L. Analysis of Conformational Coverage. 1. Validation and Estimation of Coverage. J. Chem. Inf. Comput. Sci. 1995, 35, 285-294.
44. Smellie, A.; Kahn, S. D.; Teig, S. L. Analysis of Conformational Coverage, 2. Application of Conformational Models. J. Chem. Inf. Comput. Sci. 1995, 35, 295-304.
45. Brooks, B. R.; Bruccoleri, R. E.; Olafson, B. D.; States, D. J.; Swaminathan, S.; Karplus, M. CHARMM: a Program for Macromolecular Energy, Minimization, and Dynamics Calculations. J. Comput. Chem. 1983, 4, 187-217.
46. Catalyst, version 4.9; Accelrys Inc.: San Diego, CA, 2003.
47. Briens, F.; Bureau, R.; Rault, S. Applicability of Catalyst in Ecotoxicology, a New Promising Tool for 3D-QSAR: Study of Chlorophenols. Ecotoxicol. Environ. Saf. 1999, 43, 241-251.
48. Qin, W.; Luo, H.; Nomura, T.; Hayashi, N.; Yamashita, T.; Murakami, S. Oligomeric Interaction of Hepatitis C Virus NS5B Is Critical for Catalytic Activity of RNA-Dependent RNA Polymerase. J. Biol. Chem. 2002, 277, 2132-2137.
49. Yamashita, T.; Kaneko, S.; Shirota, Y.; Qin, W.; Nomura, T.; Kobayashi, K.; Murakami, S. RNA-Dependent RNA Polymerase Activity of the Soluble Recombinant Hepatitis C Virus NS5B Protein Truncated at the C-Terminal Region. J. Biol. Chem. 1998, 273, 15479-15486.