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    • Egypt has the highest prevalence of HCV worldwide with almos

    2021-10-11

    Egypt has the highest prevalence of HCV worldwide with almost 20% of the population being infected. The HCV subtype 4a belonging to genotype 4 (HCV-4) is the most common genotype in Egypt [25], [26], [27], [28]. The sequence of the NS5A/NS5B junction for the Egyptian genotype 4 is Glu-Asp-Val-Val-Cys-Cys consequently, the hexa-peptide NH2-P6-P5-P4-P3-P2-P1-OH represents a natural substrate [27], [29]. Computer-Aided Drug Design (CADD) technology can be divided into three categories: structure-based drug design, ligand-based drug design, and validation by molecular dynamics simulation. The structure-based drug design is an essential field in CADD involving docking of small molecules into macromolecules, especially protein targets. Protein–ligand or protein–protein docking is a computational technology used to predict the orientation of a ligand when it is bound to a protein receptor or enzyme. The process involves applying a scoring function to estimate the likelihood that a ligand will bind to protein with high affinity for further biochemical experiments and developments [30], [31], [32], [33], [34]. Cellulose is a linear polymer that has the same β-(1-4)-d-glucopyranose units backbone as chitosan, except that the acetamide is replaced by 2-hydroxy group. It forms crystals, where intra-molecular and intra-strand hydrogen bonds hold the network flat allowing the more hydrophobic ribbon faces to stack [35]. The similarity of cellulose and chitosan in primary structures suggests that they may be sufficiently similar to facilitate the formation of a homogeneous composite [36]. The present work investigates the potential antiviral properties of compounds characterized by a cellulose po1 synthesis with hexa-peptide functionalities at different positions. This design is based on previous experimental work making use po1 synthesis of simple sugars (e.g. β-glucose, where cellulose is built of units of glucose) as a scaffold in many suggested antiviral inhibitors (especially HCV protease inhibitors) [37], [38], [39], [40], [41], [42]. On the other hand, experimental work on peptide inhibitors (such as tri, tetra or hexa-peptides) demonstrated HCV NS3 protease inhibition [43], [44], [45], [46], [47].
    Results and discussion The theoretical electronic and QSAR properties of some novel peptidomimetic HCV NS3 protease inhibitors are presented. These suggested inhibitors are targeting the most common genotype (genotype 4) in Egypt [56], [57], [58]. The NS5A/NS5B junction is represents one of the four natural substrate cleavage sites for HCV NS3 protease. The sequence of the NS5A/NS5B junction for Egyptian genotype 4 is Glu-Asp-Val-Val-Cys-Cys and is shown in Scheme 1. The contemplated target compounds contain a hexa-peptide functionality of cellulose as competitive peptidomimetic inhibitors for HCV NS3 protease, especially genotype 4. From previous studies, the suggested inhibitor compounds with dimer cellulose have QSAR properties better than those consisting of monomer cellulose [57], [58]. The protein–ligand docking calculations are simulated in this study to investigate the inhibition activity and interaction modes of these selected compounds with the HCV NS3 protease active site and are compared with a natural substrate. The selected and investigated compounds are built up from dimer cellulose and the hexa-peptide sequences Glu-Asp-Val-Val-Cys-Cys. These hexa-peptide sequences with dimer cellulose are modeled at positions 2, 3, 6, 2′, 3′ or 6′ (Scheme 2). Fig. 1 shows the general orientation mode of interactions between the suggested peptidomimetic inhibitors and the HCV-NS3 protease active site (His57, Asp81, Ser139) and Gly137. The docking simulation systems and detailed mode of interaction between HCV NS3 protease and studied compounds as well as the natural substrate were calculated through docking simulation and presented in Fig. 2. The red dashed lines in Fig. 2 represent the hydrogen bonds (H-bonds) formed within the investigated compounds or ligands, while the yellow dashed lines represent the hydrogen bonds (H-bonds) formed between the investigated compounds or ligands and the HCV NS3 protease residues. The number of H-bonds which are formed in docking systems either between the investigated compounds and HCV NS3 protease or in investigated compounds are listed in Table 1. The number of hydrogen bonds within the studied ligands or compounds is assumed to provide an indication of the stability of the ligand through the interaction with the HCV NS4 protease. Increases in hydrogen bonds are likely to reflect more stability in the docking system. Table 1 presents the total energy of docking systems, a final docking score and the binding energy in Kcal/mol. Base on Fig. 2, the mode of binding and the interaction of substrate and introduced compounds within the binding site residues in HCV NS3 protease are now described in detail.