Computational Approaches for the Discovery of Novel Hepatitis C Virus NS3/4A and NS5B Inhibitors

Computational Approaches for the Discovery of Novel Hepatitis C Virus NS3/4A and NS5B Inhibitors

Khac-Minh Thai, Quoc-Hiep Dong, Thi-Thanh-Lan Nguyen, Duy-Phong Le, Minh-Tri Le, Thanh-Dao Tran
DOI: 10.4018/978-1-4666-8136-1.ch009
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Nonstructural 5B (NS5B) polymerase and Nonstructural 3/4A (NS3/4A) protease have proven to be promising targets for the development of anti-HCV (Hepatitis C Virus) agents. The NS5B polymerase is of paramount importance in HCV viral replication; therefore, employing NS5B inhibitors was considered an effective way for the treatment of HCV. Identifying inhibitors against NS3/4A serine protease represents another attractive approach applied in anti-HCV drug discovery, which is evidenced by its crucial role of in the biogenesis of the viral replication activity. In this chapter, many different computational approaches including Quantitative Structure-Activity Relationship (QSAR) and virtual screening in anti-HCV drug discovery were considered and discussed in detail. Virtual Screening (VS) techniques, including ligand-based and structure-based, and QSAR have been utilized for the discovery of NS5B inhibitors. Moreover, using various in silico protocols and workflows, a number of studies have been conducted with an aim of identifying potential NS3/4A blockage agents.
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Hcv Genome And Structure

HCV Genome

HCV is an enveloped, positive-sense and single-stranded RNA virus approximately 9600 nucleotides in length. The significant genetic diversity was exhibited in HCV genome due to its highly error prone RNA polymerase, which makes difficulties for vaccine development and the discovery of anti–HCV agents (Francesco et al., 2005). 6 major HCV genotypes have been identified with the difference of over 30% in nucleotide sequences among each of them (Simmonds et al., 2005). RNA of HCV includes one continuous open reading frame bounded by two nontranslated regions (NTRs) at 5’ and 3’ ends. 5’ NTR constitutes the internal ribosome entry site (IRES), which plays the role as a starting point of cap-independent translation of HCV genome to produce a single polyprotein (Honda et al., 1996). The polyprotein is in turn split by both host cell and virus proteases into 10 different viral proteins with various functions and characteristics (Alvisi et al., 2011).

Structural Proteins

HCV core contains a nucleocapsid protein which fulfills numerous important functions involving RNA binding, immune modulation, signaling, and autophagy. The core protein is surrounded by HCV E1/E2 which are glycosylated envelope glycoproteins. Additionally, glycosylated proteins are able to neutralize antibody, which is attributed to ineffective immune and HCV persistence (Kaplan et al., 2007). Furthermore, there is another ion channel protein, namely p7, which is of great importance in viral assembly and release.

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