In silico studies of medicinal compounds against hepatitis C capsid protein from north India

Abstract

Hepatitis viral infection is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Over one million people are estimated to be persistently infected with hepatitis C virus (HCV) worldwide. As capsid core protein is the key element in spreading HCV; hence, it is considered to be the superlative target of antiviral compounds. Novel drug inhibitors of HCV are in need to complement or replace the current treatments such as pegylated interferon's and ribavirin as they are partially booming and beset with various side effects. Our study was conducted to predict 3D structure of capsid core protein of HCV from northern part of India. Core, the capsid protein of HCV, handles the assembly and packaging of HCV RNA genome and is the least variable of all the ten HCV proteins among the six HCV genotypes. Therefore, we screened four phytochemicals inhibitors that are known to disrupt the interactions of core and other HCV proteins such as (a) epigallocatechin gallate (EGCG), (b) ladanein, (c) naringenin, and (d) silybin extracted from medicinal plants; targeted against active site of residues of HCV-genotype 3 (G3) (Q68867) and its subtypes 3b (Q68861) and 3g (Q68865) from north India. To study the inhibitory activity of the recruited flavonoids, we conducted a quantitative structure-activity relationship (QSAR). Furthermore, docking interaction suggests that EGCG showed a maximum number of hydrogen bond (H-bond) interactions with all the three modeled capsid proteins with high interaction energy followed by naringenin and silybin. Thus, our results strongly correlate the inhibitory activity of the selected bioflavonoid. Finally, the dynamic predicted capsid protein molecule of HCV virion provides a general avenue to target structure-based antiviral compounds that support the hypothesis that the screened inhibitors for viral capsid might constitute new class of potent agents but further confirmation is necessary using in vitro and in vivo studies.

Keywords: capsid protein; docking; hepatitis C virus; hepatocellular carcinoma; inhibitors.

Figure 1

Expanded BLAST search conducted for three HCV subtypes from north India. Maximum homology is denoted by linear line (green color) whereas poor identity with coverage is denoted in fragmented line (black color). (A) Protein BLAST of HCV-G3 (Q688867), (B) subtype 3b alignment (Q688861), and (C) subtype 3g alignment (Q688865).

Figure 2

Comparison of protein sequences and its conserved residues. Unique identifiers between target and template sequence were analyzed. Each AA is identified by specific color and consensus conserved residues are labeled in capital letters. 1XCQ and 1N64 shared only 15% and 35% homology with the target sequence, respectively.

Figure 3

Phylogram chart of capsid core proteins in HCV genotypes. Tree represents strong correlation among both template and subtypes of different HCV genotypes capsid protein sequence as their branch length leading to these nodes is very close. The unit change in AA sequence among the species is 0.1%.

Figure 4

Comparison of Ramachandran plots between template and target proteins. (A) Plot for HCV G3, (B) model 3b, (C) model 3g, (D) template-1XCQ, and (E) template-1N64. Both the chosen templates indicated 0% in disallowed region. The three models exhibit good reliability of the predicted structure.

Figure 5

Graphical representations of the best poses within the potential drug binding site of the core protein. (A) Interaction of EGCG within the binding pockets of G3, (B) EGCG formed nine H-bond interactions with model 3b in its active binding sites, and (C) subtype 3g and its potential binding site for drug EGCG. The modeled protein is represented in ribbon like structure as backbone with alpha helix (blue color) and beta sheets (red color), ribbon like structure (grey color). Selected ligand is shown in ball and stick shape (green color) and hydrogen interactions in blue lines.

Figure 6

The 3D representations of the second best pose for each subtype cluster. (A) Naringenin formed nine H-bonds with the core of G3, (B) silybin interacting with core subtype 3b, and (C) docking of silybin to the core protein. Surface of the protein is colored in purple with ligand in the shape of ball and stick structure.