Blog
About

14
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Evaluating Andrographolide as a Potent Inhibitor of NS3-4A Protease and Its Drug-Resistant Mutants Using In Silico Approaches

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Current combination therapy of PEG-INF and ribavirin against the Hepatitis C Virus (HCV) genotype-1 infections is ineffective in maintaining sustained viral response in 50% of the infection cases. New compounds in the form of protease inhibitors can complement the combination therapy. Asunaprevir is new to the drug regiment as the NS3-4A protease inhibitor, but it is susceptible to two mutations, namely, R155K and D168A in the protein. Thus, in our study, we sought to evaluate Andrographolide, a labdane-diterpenoid from the Andrographis paniculata plant as an effective compound for inhibiting the NS3-4A protease as well as its concomitant drug-resistant mutants by using molecular docking and dynamic simulations. Our study shows that Andrographolide has best docking scores of −15.0862, −15.2322, and −13.9072 compared to those of Asunaprevir −3.7159, −2.6431, and −5.4149 with wild-type R155K and D168A mutants, respectively. Also, as shown in the MD simulations, the compound was good in binding the target proteins and maintains strong bonds causing very less to negligible perturbation in the protein backbone structures. Our results validate the susceptibility of Asunaprevir to protein variants as seen from our docking studies and trajectory period analysis. Therefore, from our study, we hope to add one more option in the drug regiment to tackle drug resistance in HCV infections.

          Related collections

          Most cited references 34

          • Record: found
          • Abstract: found
          • Article: not found

          Evolving epidemiology of hepatitis C virus.

           D Lavanchy (2011)
          More than 20 years after the discovery of the hepatitis C virus (HCV), it is now well established that HCV is of global importance affecting all countries, leading to a major global health problem that requires widespread active interventions for its prevention and control. Chronic hepatitis C was linked to the development of cirrhosis and hepatocellular carcinoma in many areas of the world. Current epidemiological assessments have identified complex patterns with highly variable local prevalence rates between countries and within countries. HCV infection patterns have not significantly changed in most parts of the world since 1997, when first analyzed, partly due to the lack of new and more accurate data. The assessment of the national HCV prevalence and transmission modes should be completed to enable national authorities to prioritize preventive measures and to make the most appropriate use of available resources. The 'patchy' epidemiological situation in some areas will continue to complicate the task of the establishment of global, regional and national base line data. The present assessment finds a global prevalence of 2.35%, affecting 160 million chronically infected individuals. There is an urgent need for more accurate Information on the costs and burden of HCV to society. Twenty-one year after the discovery of HCV, the assessment is far from being complete and little progress has been made in the past 10 years in many countries. In some countries significant increases have been reported and this may also apply to countries were insufficient data exist. A safe and efficient vaccine against HCV is urgently needed. © 2011 The Author. Clinical Microbiology and Infection © 2011 European Society of Clinical Microbiology and Infectious Diseases.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Lead- and drug-like compounds: the rule-of-five revolution.

             C Lipinski (2004)
            Citations in CAS SciFinder to the rule-of-five (RO5) publication will exceed 1000 by year-end 2004. Trends in the RO5 literature explosion that can be discerned are the further definitions of drug-like. This topic is explored in terms of drug-like physicochemical features, drug-like structural features, a comparison of drug-like and non-drug-like in drug discovery and a discussion of how drug-like features relate to clinical success. Physicochemical features of CNS drugs and features related to CNS blood-brain transporter affinity are briefly reviewed. Recent literature on features of non-oral drugs is reviewed and how features of lead-like compounds differ from those of drug-like compounds is discussed. Most recently, partly driven by NIH roadmap initiatives, considerations have arisen as to what tool-like means in the search for chemical tools to probe biology space. All these topics frame the scope of this short review/perspective.: © 2004 Elsevier Ltd . All rights reserved.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection.

              All-oral combination therapy is desirable for patients with chronic hepatitis C virus (HCV) infection. We evaluated daclatasvir (an HCV NS5A replication complex inhibitor) plus sofosbuvir (a nucleotide analogue HCV NS5B polymerase inhibitor) in patients infected with HCV genotype 1, 2, or 3. In this open-label study, we initially randomly assigned 44 previously untreated patients with HCV genotype 1 infection and 44 patients infected with HCV genotype 2 or 3 to daclatasvir at a dose of 60 mg orally once daily plus sofosbuvir at a dose of 400 mg orally once daily, with or without ribavirin, for 24 weeks. The study was expanded to include 123 additional patients with genotype 1 infection who were randomly assigned to daclatasvir plus sofosbuvir, with or without ribavirin, for 12 weeks (82 previously untreated patients) or 24 weeks (41 patients who had previous virologic failure with telaprevir or boceprevir plus peginterferon alfa-ribavirin). The primary end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter) at week 12 after the end of therapy. Overall, 211 patients received treatment. Among patients with genotype 1 infection, 98% of 126 previously untreated patients and 98% of 41 patients who did not have a sustained virologic response with HCV protease inhibitors had a sustained virologic response at week 12 after the end of therapy. A total of 92% of 26 patients with genotype 2 infection and 89% of 18 patients with genotype 3 infection had a sustained virologic response at week 12. High rates of sustained virologic response at week 12 were observed among patients with HCV subtypes 1a and 1b (98% and 100%, respectively) and those with CC and non-CC IL28B genotypes (93% and 98%, respectively), as well as among patients who received ribavirin and those who did not (94% and 98%, respectively). The most common adverse events were fatigue, headache, and nausea. Once-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients infected with HCV genotype 1, 2, or 3, including patients with no response to prior therapy with telaprevir or boceprevir. (Funded by Bristol-Myers Squibb and Pharmasset (Gilead); A1444040 ClinicalTrials.gov number, NCT01359644.).
                Bookmark

                Author and article information

                Journal
                Adv Virol
                Adv Virol
                AV
                Advances in Virology
                Hindawi Publishing Corporation
                1687-8639
                1687-8647
                2015
                26 October 2015
                : 2015
                Affiliations
                Department of Biotechnology, Siddaganga Institute of Technology, Tumkur, Karnataka 572 103, India
                Author notes
                *Vivek Chandramohan: vivek.bioinf@ 123456gmail.com

                Academic Editor: Jay C. Brown

                10.1155/2015/972067
                4637434
                Copyright © 2015 Vivek Chandramohan et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Research Article

                Microbiology & Virology

                Comments

                Comment on this article