Evaluating Andrographolide as a Potent Inhibitor of NS3-4A Protease and Its Drug-Resistant Mutants UsingIn SilicoApproaches

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.

In-silico design and molecular docking evaluation of peptides derivatives from bacteriocins and porcine beta defensin-2 as inhibitors of Hepatitis E virus capsid protein

“…Hepatitis C virus (HCV) is a widely studied viral model, and using CADD methods a natural bicycle diterpene was evaluated by molecular docking. This diterpene interacts with both, the native and the mutated structures of the HCV NS3-4A protease, with a docking score of -15.1 kcal/mol, and this interaction was mediated mainly by the presence of hydrogen bonds between the ligand and S, A and H amino acids in the target protein [5]; in our study, the best interaction between subti1 and HEV capsid protein showed a docking score of -7.0 kcal/mol and was also mediated by the presence of A504 in chain A of the HEV capsid protein, forming two hydrogen bonds ( Table 2). In a similar way, bioflavonoids showed a promissory anti-HCV helicase activity, with high docking scores and with residues D and S as the main amino acids participating in the interaction [13]; these residues were also mediating the interaction of HEV capsid protein and the AVPs designed in our study, suggesting that D and S could be crucial for AVPs interactions ( Table 2).…”

Crosstalk between endoplasmic reticulum stress and anti-viral activities: A novel therapeutic target for COVID-19

“…Moreover, several clinical trials demonstrate its positive effects on infectious disease, autoimmune disorders and it has a potential effect against viral defenses [44,50,52]. Moreover, it exerts anti-viral activity towards a number of different viruses including HIV, hepatitis B, herpes simplex, influenza, hepatitis C, chikungunya virus (CHIKV), Epstein-Barr virus (EBV), human papillomavirus (HPV) dengue virus (DENV) and others [51,56,57,[61][62][63][64][65][66][67][68][69][70][71][72]. Recent studies showed that andrographolide is a potential inhibitor of the main protease of SARS-CoV-2 through in silico studies, such as molecular docking, target analysis, toxicity prediction and ADME prediction (absorption, distribution, metabolism, and excretion) [57].…”

Hepatitis C: From inflammatory pathogenesis to anti-inflammatory/hepatoprotective therapy

“…Moreover, andrographolide was reported to inhibit HCV protein synthesis, RNA replication and infection[101]. Detailed mechanisms showed that andrographolide activates p38 MAPK phosphorylation and stimulates Nrf2-mediated heme oxygenase (HO)-1 expression, thereby increasing the amounts of its metabolite biliverdin, which was found to activate the antiviral IFN response and suppress HCV NS3/4A protease activity[101,102]. These findings support a clinical trial of andrographolide and its derivatives for the treatment of severe CHC.…”