Abstract
Hepatitis C Virus (HCV) is the key cause of chronic and severe liver diseases. The recent direct-acting antiviral agents have shown the clinical success on HCV-related diseases, but the rapid HCV mutations of the virus highlight the sustaining necessity to develop new drugs. p7, the viroporin protein from HCV, has been sought after as a potential anti-HCV drug target. Several classes of compounds, such as amantadine and rimantadine have been testified for p7 inhibition. However, the efficacies of these compounds are not high. Here, we screened some novel p7 inhibitors with amantadine scaffold for the inhibitor development. The dissociation constant (Kd) of 42 ARD-series compounds were determined by nuclear magnetic resonance (NMR) titrations. The efficacies of the two best inhibitors, ARD87 and ARD112, were further confirmed using viral production assay. The binding mode analysis and binding stability for the strongest inhibitor were deciphered by molecular dynamics (MD) simulation. These ARD-series compounds together with 49 previously published compounds were further analyzed by molecular docking. Key pharmacophores were identified among the structure-similar compounds. Our studies suggest that different functional groups are highly correlated with the efficacy for inhibiting p7 of HCV, in which hydrophobic interactions are the dominant forces for the inhibition potency. Our findings provide guiding principles for designing higher affinity inhibitors of p7 as potential anti-HCV drug candidates.
Highlights
IntroductionHepatitis C is a type of chronic liver diseases that only occurs in humans and chimpanzees in a slow and unnoticeable manner [1]
Using molecular dynamics (MD) simulations, we investigated the binding modes and binding stability for the strongest inhibitor, ARD112
Amantadine only showed weak inhibition activities on Hepatitis C Virus (HCV) p7, so based on the structural knowledge on the amantadine or rimantadine binding to p7, we designed a series of amantadine or rimantadine derivatives (ARD-series)
Summary
Hepatitis C is a type of chronic liver diseases that only occurs in humans and chimpanzees in a slow and unnoticeable manner [1]. Chronic hepatitis C may lead to liver cirrhosis, fibrosis and even hepatocellular carcinoma. It is currently estimated that hepatitis C infection affects approximately 185 million people worldwide which causes up to. 500,000 deaths every year [2,3]. For a long-standing period, hepatitis C has been a global health problem due to the lack of an effective vaccine or approved therapies targeting on hepatitis C virus (HCV), the major cause of hepatitis C. HCV is a positivelystranded RNA virus that was first discovered in 1989 [4].
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