Abstract
The current available treatment for hepatitis C virus (HCV)—the causative of liver cirrhosis and development of liver cancer—is a dual therapy using modified interferon and ribavirin. While this regimen increases the sustained viral response rate up to 40–80 % in different genotypes, unfortunately, it is poorly tolerated by patients. PSI-7977, a prodrug for PSI-7409, is a Non-Structural 5b (NS5b) polymerase nucleoside inhibitor that is currently in phase III clinical trials. The activated PSI-7977 is a direct acting antiviral (DAA) drug that acts on NS5b polymerase of HCV through a coordination bond with the two Mg+2 present at the GDD active site motif. The present work utilizes a molecular modeling approach for studying the interaction between the activated PSI-7977 and the 12 amino acids constituting a 5 Å region surrounding the GDD active triad motif for HCV genotypes 1a, 2b, 3b and 4a. The analysis of the interaction parameters suggests that PSI-7977 is probably a better DAA drug for HCV genotypes 1a and 3b rather than genotypes 2b and 4a.
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Abbreviations
- NS3:
-
Non-structural 3 proteins
- NS5b:
-
Non-structural 5b protein
- RdRp:
-
RNA dependent RNA polymerase
- SVR:
-
Sustained viral response
- DAA:
-
Direct acting antivirus
- HCV:
-
Hepatitis C virus
- NI:
-
Nucleotide inhibitor
- NNI:
-
Non nucleotide inhibitor
- HOMO:
-
Highest occupied molecular orbital
- LUMO:
-
Lowest unoccupied molecular orbital
- PHYRE:
-
Protein Homology/anologY Recognition Engine
- SCOP:
-
Structure classification of proteins
- SAVES:
-
Structure analysis and verification server
References
Andreeva A, Howorth D, Brenner SE, Hubbard TJP, Chothia C, Murzin AG (2004) Nucleic Acids Res 32:D226–D229
Andreeva A, Howorth D, Chandonia JM, Brenner SE, Hubbard TJP, Chothia C, Murzin AG (2008) Nucleic Acids Res 36:D419–D425
Bahgat MM, Ibrahim AA, Abd-Elshafy DN, Mesalam AA, Gewaid HE, Ismaeil AAE, El-Waseef AM, Maghraby AS, Barakat AB, El-Far MA, Ghanem HEA, Mohamed AM, Ali MA (2009) Arch Virol 154:1649–1657
Beaulieu PL, Gillard J, Jolicoeur E, Duan J, Garneau M, Kukolj G, Poupart MA (2011) Bioorg Med Chem Lett 21:3658–3663
Chamberlain RW, Adams N, Saeed AA, Simmonds P, Elliott RM (1997) Gen Virol 78:1341–1347
Chen YL, Tang J, Kesler MJ, Sham YY, Vince R, Geraghty RJ, Wang Z (2012) Bioorg Med Chem 20:467–479
Chevaliez S, Asselah T (2011) Cl Res Hepato Gastro 35:S31–S41
Chevaliez S, Pawlotsky JM (2007) Adv Drug Deliv Rev 59:1222–1241
Chinnaswamy S, Cai H, Kao C (2010) Virus Adap Treat 2:73–89
Choo AQ, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M (1989) Science 244:359–362
Conte LL, Brenner SE, Hubbard TJP, Chothia C, Murzin AG (2002) Nucleic Acids Res 30:264–267
Das D, Hong J, Chen SH, Wang G, Beigelman L, Seiwert SD, Buckman BO (2011) Bioorg Med Chem 19:4690–4703
De Francesco R, Carfí A (2007) Adv Drug Deliv Rev 59:1242–1262
De Francesco R, Tomei L, Altamura S, Summa V, Migliaccio G (2003) Antivir Res 58:1–16
Delang L, Vliegen I, Leyssen P, Neyts J (2012) J Hepatol 56:41–48
Doublie S, Ellenbergert T (1998) Curr Opin Struc Biol 8:704–712
Elshemey WM, Elfiky AA, Gawad WA (2010) Protein J 29:545–550
Farrell DO, Trowbridge R, Rowlands D, Ja J (2003) J Mol Biol 326:1025–1035
Firpi RJ, Nelson DR (2007) Arch Med Res 38:678–690
Gelman MA, Glenn JS (2010) Trends Mol Med 17:34–46
Genovese D, Dettori S, Argentini C, Villano U, Chionne P, Angelico M, Rapicetta M (2005) J Clin Microbiol 43:1902–1909
Huang Z, Murray MG, Secrist JA, Box PO (2006) Antivir Res 71:351–362
Humphrey W, Dalke A, Schulten K (1996) J Mol Graph 14:33–38
Ibrahim M, Saleh NA, Elshemey WM, Elsayed AA (2012) Med Chem 8:6–10
Ibrahim M, Saleh NA, Jameel A, Elshemey WM, Elsayed AA (2010) Spectrochim Acta A 75:702–709
Kelley LA, Sternberg MJE (2009) Nat Protocol 4:363–371
Lemon SM, McKeating JA, Pietschmann T, Frick DN, Glenn JS, Tellinghuisen TL, Symons J, Furman PA (2010) Antivir Res 86:79–92
Massariol MJ, Zhao S, Marquis M, Thibeault D, White PW (2010) Biochem Biophys Res Commun 391:692–697
Mayhoub AS (2012) Bioorg Med Chem 20:3150–3161
Murakami E, Tolstykh T, Bao H, Niu C, Steuer HMM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM, Otto MJ, Sofia MJ, Furman PA (2010) J Biol Chem 285:34337–34347
Murzin AG, Brenner SE, Hubbard TJP, Chothia C (1995) J Mol Biol 247:536–540
Sarrazin C, Hézode C, Zeuzem S, Pawlotsky JM (2012) J Hepatol 56:S88–S100
Suzuki T, Ishii K, Aizaki H, Wakita T (2007) Adv Drug Deliv Rev 59:1200–1212
Talele TT, Arora P, Kulkarni SS, Patel MR, Singh S, Chudayeu M, Kaushik-Basu N (2010) Bioorg Med Chem 18:4630–4638
Thompson AJ, Locarnini SA, Beard MR (2011) Curr Opin Virol 1:599–606
Yan S, Appleby T, Larson G, Wu JZ, Hamatake R, Hong Z, Yao N (2006) Bioorg Med Chem Lett 16:5888–5891
Yang PL, Gao M, Lin K, Liu Q, Villareal VA (2011) Curr Opin Virol 1:607–616
Acknowledgments
The authors are thankful to Dr. Noha A. saleh, Bahaa M. Abdelazeim, Ahmed A. Ezzat and Alaa M. ElGohary for their helpful comments and support for this work.
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Elfiky, A.A., Elshemey, W.M., Gawad, W.A. et al. Molecular Modeling Comparison of the Performance of NS5b Polymerase Inhibitor (PSI-7977) on Prevalent HCV Genotypes. Protein J 32, 75–80 (2013). https://doi.org/10.1007/s10930-013-9462-9
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DOI: https://doi.org/10.1007/s10930-013-9462-9