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  • Unfortunately the approved drugs suffer from failure in many

    2021-10-25

    Unfortunately, the approved drugs suffer from failure in many cases [5,6]. Several mutations occur in the binding site of NS3/4A protease, which affect drug binding and cause drug resistance [13]. It is a big challenge and needs more efforts to be done. This is the reason why research is still concerned with the design of new drugs and the search for new strategies to fight against drug resistance [[14], [15], [16], [17], [18]]. Also, there are genotypes that are still difficult to treat, such as genotypes 2 and 3 [2,6,13,19]. They have natural polymorphisms (variants) that cause resistance to several drugs [13,19]. Several studies report that the dynamics of different genotypes are not conserved [[19], [20], [21]]. This explains their different enzymatic activities, drug affinities and response to treatment. The physicochemical and geometrical characteristics of 5046 sale are not conserved as well [[19], [20], [21]]. Molecular modeling techniques are well established tools for the study of the dynamics, energetics and interactions of biomolecules, especially proteins [[22], [23], [24], [25], [26]]. They are widely used to study protein – ligand interactions and to predict the binding mode of a drug inside the binding site of a protein [8,9]. Molecular docking is one of these techniques that is able to predict the binding mode of drugs with protein (i.e. protein – drug complex conformation) and score of complex (i.e. binding free energy of complex) [[27], [28], [29]].
    Materials and methods
    Results and discussion
    Conclusion
    Introduction It is estimated that 71 million people worldwide are chronically infected with hepatitis C virus (HCV) and the number of deaths each year mostly from cirrhosis and hepatocellular carcinoma is approximately 399,000 [1]. An important clinical aspect of hepatitis C is the high rate of progression to chronicity observed in about 85% of individuals infected by HCV. A substantial fraction of these chronic carriers might develop progressive liver fibrosis, eventually leading to cirrhosis and hepatocellular carcinoma (HCC) [2]. HCV is classified in seven genotypes (1–7) and 67 subtypes [3]. The most common subtypes in Western countries are 1a and 1b [4]. Until 2011, the therapy for chronic hepatitis C was based in a combination of pegylated-interferon and ribavirin (peg-IFN/RBV), a long-term therapy that, besides the severe undesirable side effects [5], had not produced encouraging results in sustained virological response (SVR) mainly for patients infected with HCV genotype 1 [6]. Due to this unsatisfactory therapeutic approach, a regimen with fewer side effects, reduced rates of patient withdrawal and increased effectiveness in preventing the progression to decompensated cirrhosis and HCC has been the focus of several studies of drug development and clinical trials during the last decade. Advances in cell cultures lineages permissive to HCV infection had represented a milestone in understanding about viral life cycle. Along with the three-dimensional 5046 sale computational modelling of viral proteins, several molecules capable of a specific inhibition of proteins acting in different stages of virus replication have been developed and nominated as direct-acting antiviral drugs (DAAs) [7]. Among the targets for DAA is the HCV NS3 serine protease, a protein that forms a non-covalent complex with NS4A and is responsible for the cleavage of the non-structural portion of the translated viral polyprotein. In 2013, first-wave, first-generation drugs telaprevir and boceprevir was the first protease inhibitors (PIs) incorporated in Brazilian Clinical Guidelines for the treatment of patients infected with HCV genotype 1. Based on this 2013 Clinical Guideline, telaprevir could be used for both naïve and experienced patients whereas boceprevir was only indicated for treatment-naïve patients with advanced fibrosis METAVIR F3 and F4. Its combination with peg-IFN/RBV yielded an improvement in the SVR rate up to 75% [8], [9], [10], [11], [12]. Nonetheless, significant side effects and unsatisfactory efficiency against genotype 1 highlighted the necessity of development of compounds targeting different viral proteins in order to achieve higher SVR rates and viral clearance. More recently, other HCV PIs have been incorporated to Clinical Guidelines and can be prescribed irrespective of patients’ treatment records. Simeprevir, a second-wave, first-generation NS3/4A PI, daclatasvir (NS5A inhibitor) and sofosbuvir (NS5B polymerase inhibitor) were approved for clinical use in Brazil in 2015. Its genotypic coverage is broader than that of the first-wave drugs, including at least genotypes 1, 2, and 4 [13]. In 2017, paritaprevir in combination with ombitasvir, ritonavir and dasabuvir has been licensed in Brazil for subtype 1a patients without cirrhosis and for subtype 1b patients with compensated cirrhosis (Child–Pugh A). A second-generation PI, grazoprevir, co-administrated with elbasvir was incorporated in clinical protocol for patients infected with HCV genotype 1 and 4. Pangenotypic PIs, such as glecaprevir and voxilaprevir, are not yet registered in Brazilian regulatory agency however represents a promising alternative for patients with or without cirrhosis.