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Molecular Modeling Comparison of the Performance of NS5b Polymerase Inhibitor (PSI-7977) on Prevalent HCV Genotypes

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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

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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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Correspondence to Abdo A. Elfiky.

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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

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