Skip to main content
SpringerLink
Log in

Virtual screening of imidazole analogs as potential hepatitis C virus NS5B polymerase inhibitors

  • Original Paper
  • Published:
Chemical Papers Aims and scope Submit manuscript

Abstract

Hepatitis C virus (HCV) infection is a global health threat and current therapies warrant the need for novel HCV therapies. Several synthetic analogs targeting HCV serine protease and RNA-dependent RNA polymerase have entered clinical development. To investigate the novel HCV NS5B RdRp polymerase inhibitor, screening of a designed data set consisting of benzimidazole analogs by the FlexX docking approach was performed. Binding interactions at the active sites (PDB ID: 2DXS) were evaluated leading to the rationalization of further synthesis and evaluation procedures.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Anilkumar, G. N., Selyutin, O., Rosenblum, S. B., Zeng, Q. B., Jiang, Y. H., Chan, T. Y., Pu, H. Y., Wang, L., Bennett, F., Chen, K. X., Lesburg, C. A., Duca, J. S., Gavalas, S., Huang, Y. H., Pinto, P., Sannigrahi, M., Velazquez, F., Venkataraman, S., Vilbubhan, B., Agrawal, S., Ferrari, E., Jiang, C. K., Huang, H. C., Shih, N. Y., Njoroge, F. G., & Kozlowski, J. A. (2012). II. Novel HCV NS5B polymerase inhibitors: Discovery of indole C2 aryl sulfonamides. Bioorganic & Medicinal Chemistry Letters, 22, 713–717. DOI: 10.1016/j.bmcl.2011.10.041.

    Article  CAS  Google Scholar 

  • Beaulieu, P. L. (2007). Non-nucleoside inhibitors of the HCV NS5B polymerase: progress in the discovery and development of novel agents for the treatment of HCV infections. Current Opinion in Investigational Drugs, 8, 614–634.

    CAS  Google Scholar 

  • Beaulieu, P. L., Bös, M., Bousquet, Y., DeRoy, P., Fazal, G., Gauthier, J., Gillard, J., Goulet, S., McKercher, G., Poupart, M. A., Valois, S., & Kukolj, G. (2004). Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase: discovery of benzimidazole 5-carboxylic amide derivatives with low-nanomolar potency. Bioorganic & Medicinal Chemistry Letters, 14, 967–971. DOI: 10.1016/j.bmcl.2003.12.032.

    Article  CAS  Google Scholar 

  • Behrens, S. E., Tomei, L., & De Francesco, R. (1996). Identification and properties of the RNA-dependent RNA polymerase of hepatitis C virus. The EMBO Journal, 15, 12–22.

    CAS  Google Scholar 

  • BioSolveIT (2012). FlexX [computer software]. Sankt Augustin, Germany: BioSolveIT. www.biosolveit.de

    Google Scholar 

  • Biswal, B. K., Cherney, M. M., Wang, M., Chan, L., Yannopoulos, C. G., Bilimoria, D., Nicolas, O., Bedard, J., & James, M. N. (2005). Crystal structures of the RNA-dependent RNA polymerase genotype 2a of hepatitis C virus reveal two conformations and suggest mechanisms of inhibition by nonnucleoside inhibitors. The Journal of Biological Chemistry, 280, 18202–18210. DOI: 10.1074/jbc.m413410200.

    Article  CAS  Google Scholar 

  • Böhm, H. J. (1992). The computer program LUDI: A new method for the de novo design of enzyme inhibitors. Journal of Computer-Aided Molecular Design, 6, 61–78. DOI: 10.1007/bf00124387.

    Article  Google Scholar 

  • Bressanelli, S., Tomei, L., Rey, F. A., & De Francesco, R. (2002). Structural analysis of the hepatitis C virus RNA polymerase in complex with ribonucleotides. Journal of Virology, 76, 3482–3492. DOI: 10.1128/jvi.76.7.3482-3492.2002.

    Article  CAS  Google Scholar 

  • Chan, L., Reddy, T. J., Proulx, M., Das, S. K., Pereira, O., Wang, W. Y., 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. (2003). Identification of N,N-disubstituted phenylalanines as a novel class of inhibitors of hepatitis C NS5B polymerase. Journal of Medicinal Chemistry, 46, 1283–1285. DOI: 10.1021/jm0340400.

    Article  CAS  Google Scholar 

  • Chan, L., Pereira, O., Reddy, T. J., Das, S. K., Poisson, C., Courchesne, M., Proulx, M., Siddiqui, A., Yannopoulos, C. G., Nguyen-Ba, N., Roy, C., Nasturica, D., Moinet, C., Bethell, R., Hamel, M., L’Heureux, L., David, M., Nicolas, O., Courtemanche-Asselin, P., Brunette, S., Bilimoria, D., & Bedard, J. (2004). Discovery of thiophene-2-carboxylic acids as potent inhibitors of HCV NS5B polymerase and HCV subgenomic RNA replication. Part 2: Tertiary amides. Bioorganic & Medicinal Chemistry Letters, 14, 797–800. DOI: 10.1016/j.bmcl.2003.10.068.

    Article  CAS  Google Scholar 

  • Di Marco, S., Volpari, C., Tomei, L., Altamura, S., Harper, S., Narjes, F., Koch, U., Rowley, M., De Francesco, R., Migliaccio, G., & Carfí, A. (2005). Interdomain communication in hepatitis C virus polymerase abolished by small molecule inhibitors bound to a novel allosteric site. The Journal of Biological Chemistry, 280, 29765–29770. DOI: 10.1074/jbc.m505423200.

    Article  Google Scholar 

  • Doman, T. N., McGovern, S. L., Witherbee, B. J., Kasten, T. P., Kurumbail, R., Stallings, W. C., Connolly, D. T., & Shoichet, B. K. (2002). Molecular docking and high-throughput screening for novel inhibitors of protein tyrosine phosphatase-1B. Journal of Medicinal Chemistry, 45, 2213–2221. DOI: 10.1021/jm010548w.

    Article  CAS  Google Scholar 

  • Gopalsamy, A., Lim, K. T., Ciszewski, G., Park, K., Ellingboe, J. W., Bloom, J., Insaf, S., Upeslacis, J., Mansour, T. S., Krishnamurthy, G., Damarla, M., Pyatski, Y., Ho, D., Howe, A. Y. M., Orlowski, M., Feld, B., & O’Connell, J. (2004). Discovery of pyrano[3,4-b]indoles as potent and selective HCV NS5B polymerase inhibitors. Journal of Medicinal Chemistry, 47, 6603–6608. DOI: 10.1021/jm0401255.

    Article  CAS  Google Scholar 

  • Guido, R. V. C., Oliva, G., & Andricopulo, A. D. (2008). Virtual screening and its integration with modern drug design technologies. Current Medicinal Chemistry, 15, 37–46. DOI: 10.2174/092986708783330683.

    Article  CAS  Google Scholar 

  • Gupta, S. P., Samanta, S., & Patil, V. M. (2010). A 3D-QSAR study on a series of benzimidazole derivatives acting as hepatitis C virus inhibitors: application of kNN-molecular field analysis. Medicinal Chemistry, 6, 87–90.

    Article  CAS  Google Scholar 

  • Ikegashira, K., Oka, T., Hirashima, S., Noji, S., Yamanaka, H., Hara, Y., Adachi, T., Tsuruha, J. I., Doi, S., Hase, Y., Noguchi, T., Ando, I., Ogura, N., Ikeda, S., & Hashimoto, H. (2006). Discovery of conformationally constrained tetracyclic compounds as potent hepatitis C virus NS5B RNA polymerase inhibitors. Journal of Medicinal Chemistry, 49, 6950–6953. DOI: 10.1021/jm0610245.

    Article  CAS  Google Scholar 

  • Kaushik-Basu, N., Bopda-Waffo, A., Talele, T. T., Basu, A., Chen, Y., & Kucukguzel, S. G. (2008a). 4-Thiazolidinones: a novel class of hepatitis C virus NS5B polymerase inhibitors. Frontiers in Bioscience, 13, 3857–3868. DOI: 10.2741/2974.

    CAS  Google Scholar 

  • Kaushik-Basu, N., Bopda-Waffo, A., Talele, T. T., Basu, A., Costa, P. R. R., da Silva, A. J. M., Sarafianos, S. G., Noël, F. (2008b). Identification and characterization of coumestans as novel HCV NS5B polymerase inhibitors. Nucleic Acids Research, 36, 1482–1496. DOI: 10.1093/nar/gkm1178.

    Article  CAS  Google Scholar 

  • Koch, U., & Narjes, F. (2007). Recent progress in the development of inhibitors of the hepatitis C virus RNA-dependent RNA polymerase. Current Topics in Medicinal Chemistry, 7, 1302–1329.

    Article  CAS  Google Scholar 

  • Kumar, D. V., Rai, R., Brameld, K. A., Somoza, J. R., Rajagopalan, R., Janc, J. W., Xia, Y. M., Ton, T. L., Shaghafi, M. B., Hu, H. Y., Lehoux, I., To, N., Young, W. B., & Green, M. J. (2011). Quinolones as HCV NS5B polymerase inhibitors. Bioorganic & Medicinal Chemistry Letters, 21, 82–87. DOI: 10.1016/j.bmcl.2010.11.068.

    Article  CAS  Google Scholar 

  • Li, H., Tatlock, J., Linton, A., Gonzalez, J., Borchardt, A., Dragovich, P., Jewell, T., Prins, T., Zhou, R., Blazel, J., Parge, H., Love, R., Hickey, M., Doan, C., Shi, S., Duggal, R., Lewis, C., & Fuhrman, S. (2006). Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors. Bioorganic & Medicinal Chemistry Letters, 16, 4834–4838. DOI: 10.1016/j.bmcl.2006.06.065.

    Article  CAS  Google Scholar 

  • Love, R. A., Parge, H. E., Yu, X., Hickey, M. J., Diehl, W., Gao, J. J., Wriggers, H., Ekker, A., Wang, L., Thomson, J. A., Dragovich, P. S., & Fuhrman, S. A. (2003). Crystallographic identification of a noncompetitive inhibitor binding site on the hepatitis C virus NS5B RNA polymerase enzyme. Journal of Virology, 77, 7575–7581. DOI: 10.1128/jvi.77.13.7575-7581.2003.

    Article  CAS  Google Scholar 

  • Lyne, P. D. (2002). Structure-based virtual screening: an overview. Drug Discovery Today, 7, 1047–1055. DOI: 10.1016/s1359-6446(02)02483-2.

    Article  CAS  Google Scholar 

  • Lyne, P. D., Kenny, P.W., Cosgrove, D. A., Deng, C., Zabludoff, S., Wendoloski, J. J., & Ashwell, S. J. (2004). Identification of compounds with nanomolar binding affinity for checkpoint kinase-1 using knowledge-based virtual screening. Journal of Medicinal Chemistry, 47, 1962–1968. DOI: 10.1021/jm030504i.

    Article  CAS  Google Scholar 

  • Moradpour, D., Penin, F., & Rice, C. M. (2007). Replication of hepatitis C virus. Nature Reviews Microbiology, 5, 453–463. DOI: 10.1038/nrmicro1645.

    Article  CAS  Google Scholar 

  • Ontoria, J. M., Martín Hernando, J. I., Malancona, S., Attenni, B., Stansfield, I., Conte, I., Ercolani, C., Habermann, J., Ponzi, S., Di Filippo, M., Koch, U., Rowley, M., & Narjes, F. (2006). Identification of thieno[3,2-b]pyrroles as allosteric inhibitors of hepatitis C virus NS5B polymerase. Bioorganic & Medicinal Chemistry Letters, 16, 4026–4030. DOI: 10.1016/j.bmcl.2006.05.012.

    Article  CAS  Google Scholar 

  • Patel, P. D., Patel, M. R., Kaushik-Basu, N., & Talele, T. T. (2008). 3D QSAR and molecular docking studies of benzimidazole derivatives as hepatitis C virus NS5B polymerase inhibitors. Journal of Chemical Information and Modeling, 48, 42–55. DOI: 10.1021/ci700266z.

    Article  CAS  Google Scholar 

  • Patil, V. M., Gupta, S. P., & Samanta, S. (2010). A QSAR study on some series of anti-hepatitis C virus (HCV) agents. Letters in Drug Design & Discovery, 7, 139–148. DOI: 10.2174/157018010790225877.

    Article  CAS  Google Scholar 

  • Patil, V. M., Gupta, S. P., Samanta, S., & Masand, N. (2011). 3D QSAR kNN-MFA studies on thiouracil derivatives as hepatitis C virus inhibitors. Medicinal Chemistry Research, 20, 1616–1621. DOI: 10.1007/s00044-010-9435-x.

    Article  CAS  Google Scholar 

  • Powers, J. P., Piper, D. E., Li, Y., Mayorga, V., Anzola, J., Chen, J. M., Jaen, J. C., Lee, G., Liu, J. Q., Peterson, M. G., Tonn, G. R., Ye, Q. P., Walker, N. P. C., & Wang, Z. L. (2006). SAR and mode of action of novel non-nucleoside inhibitors of hepatitis C NS5b RNA polymerase. Journal of Medicinal Chemistry, 49, 1034–1046. DOI: 10.1021/jm050859x.

    Article  CAS  Google Scholar 

  • Rarey, M., Kramer, B., Lengauer, T., & Klebe, G. (1996). A fast flexible docking method using an incremental construction algorithm, Journal of Molecular Biology, 261, 470–489. DOI: 10.1006/jmbi.1996.0477.

    Article  CAS  Google Scholar 

  • Rarey, M., Kramer, B., & Lengauer, T. (1997). Multiple automatic base selection: Protein-ligand docking based on incremental construction without manual intervention. Journal of Computer Aided Molecular Design, 11, 369–384. DOI: 10.1023/a:1007913026166.

    Article  CAS  Google Scholar 

  • Rester, U. (2008). From virtuality to reality — Virtual screening in lead discovery and lead optimization: a medicinal chemistry perspective. Current Opinion in Drug Discovery & Development, 11, 559–568.

    CAS  Google Scholar 

  • Rong, F., Chow, S. Y., Yan, S. Q., Larson, G., Hong, Z., & Wu, J. (2007). Structure-activity relationship (SAR) studies of quinoxalines as novel HCV NS5B RNA-dependent RNA polymerase inhibitors. Bioorganic & Medicinal Chemistry Letters, 17, 1663–1666. DOI: 10.1016/j.bmcl.2006.12.103.

    Article  CAS  Google Scholar 

  • Shaw, A. N., Tedesco, R., Bambal, R., Chai, D. P., Concha, N. O., Darcy, M. G., Dhanak, D., Duffy, K. J., Fitch, D. M., Gates, A., Johnston, V. K., Keenan, R. M., Lin-Goerke, J., Liu, N. N., Sarisky, R. T., Wiggall, K. J., & Zimmerman, M. N. (2009). Substituted benzothiadizine inhibitors of Hepatitis C virus polymerase. Bioorganic & Medicinal Chemistry Letters, 19, 4350–4353. DOI: 10.1016/j.bmcl.2009.05.091.

    Article  CAS  Google Scholar 

  • Soriano, V., Peters, M. G., & Zeuzem, S. (2009). New therapies for hepatitis C virus infection. Clinical Infectious Diseases, 48, 313–320. DOI: 10.1086/595848.

    Article  Google Scholar 

  • Talele, T. T. (2008). Multiple allosteric pockets of HCV NS5B polymerase and its inhibitors: A structure based insight. Current Bioactive Compounds, 4, 86–109. DOI: 10.2174/157340708785294217.

    Article  CAS  Google Scholar 

  • Tedesco, R., Shaw, A. N., Bambal, R., Chai, D. P., Concha, N. O., Darcy, M. G., Dhanak, D., Fitch, D. M., Gates, A., Gerhardt, W. G., Halegoua, D. L., Han, C., Hofmann, G. A., Johnston, V. K., Kaura, A. C., Liu, N. N., Keenan, R. M., Lin-Goerke, J., Sarisky, R. T., Wiggall, K. J., Zimmerman, M. N., & Duffy, K. J. (2006). 3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones, potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase. Journal of Medicinal Chemistry, 49, 971–983. DOI: 10.1021/jm050855s.

    Article  CAS  Google Scholar 

  • Wang, Q. M., & Heinz, B. A. (2000). Recent advances in prevention and treatment of hepatitis C virus infections. Progress in Drug Research, 55, 1–32. DOI: 10.1007/978-3-0348-8385-61.

    Article  CAS  Google Scholar 

  • Yan, S. Q., Appleby, T., Larson, G., Wu, J. Z., Hamatake, R., Hong, Z., & Yao, N. H. (2006). Structure-based design of a novel thiazolone scaffold as HCV NS5B polymerase allosteric inhibitors. Bioorganic & Medicinal Chemistry Letters, 16, 5888–5891. DOI: 10.1016/j.bmcl.2006.08.056.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medicinal Chemistry Research Laboratory, School of Pharmacy, Bharat Institute of Technology, Meerut, 250 103, U. P., India

    Vaishali M. Patil

  2. Department of Applied Sciences, Meerut Institute of Engineering & Technology, Meerut, 250 005, U. P., India

    Satya P. Gupta

  3. Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi, 835 215, JH, India

    Subeer Samanta

  4. Department of Pharmacy, Lala Lajpat Rai Memorial Medical College, Meerut, 250 001, U. P., India

    Neeraj Masand

Authors
  1. Vaishali M. Patil
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Satya P. Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Subeer Samanta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Neeraj Masand
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vaishali M. Patil.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Patil, V.M., Gupta, S.P., Samanta, S. et al. Virtual screening of imidazole analogs as potential hepatitis C virus NS5B polymerase inhibitors. Chem. Pap. 67, 236–244 (2013). https://doi.org/10.2478/s11696-012-0241-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2478/s11696-012-0241-4

Keywords

Search

Navigation