Abstract
Hepatitis B virus (HBV) is the world’s most prevalent chronic viral infection. More than 350 million individuals are chronic carriers of the virus, with an estimated 2 billion infected persons. For instance, the role of HBx protein in attachment and infection is very obvious and consequently deemed as an important druggable target. Targeting the interface and discovering novel drugs greatly advanced the field of therapeutics development. Therefore, in the current study, HBx to Bcl-xL is abrogated on high-affinity carbon nanotubes using computational structural biology tools. Our analysis revealed that among the total 62 carbon fullerenes, only 13 compounds exhibited inhibitory activity against HBx, which was further confirmed through IFD-based rescoring. Structural dynamics investigation revealed stable binding, compactness, and hydrogen bonds reprogramming. Moreover, the binding free energy calculation results revealed that the top hits1-4 possess the total binding energy of −54.36 kcal/mol (hit1), −50.81 kcal/mol (hit2), −47.09 kcal/mol (hit3), and −45.59 kcal/mol for hit4. In addition, the predicted KD values and bioactivity scores further validated the inhibitory potential of these top hits. The identified compounds need further in vitro and in vivo validation to aid the treatment process of HBV.
Highlights
Hepatitis B virus (HBV) is the world’s most prevalent chronic viral infection
HBV DNA fragments are incorporated into several locations of the host genome, and the HBV X protein (HBx) gene is often overexpressed in the livers and tumors of HBV chronic carriers
It was discovered that HBx uses a Bcl-2 homology region 3 (BH3)-like motif to directly target antiapoptotic proteins Bcl-2 and Bcl-xL, causing an increase in cytosolic calcium, which is required for HBV viral replication, as well as cytotoxic effects through apoptosis and necrosis, leading to HBV pathogenesis [8]
Summary
Hepatitis B virus (HBV) is the world’s most prevalent chronic viral infection. More than 350 million individuals are chronic carriers of the virus, with an estimated 2 billion infected persons. The ability of a peptide containing the HBx-BH3-like motif (HBx-BH3-aa113–135) to pull down the native Bcl-xL protein in HepG2 cells, but not an analogous peptide with the W120A/L123A double mutations, supports this structural observation [12]. This HBx-BH3like peptide can restore HBV reproduction and transcription in HepG2 cells transfected with a replication-defective HBx-null HBV replicon but not an analogous peptide with the W120A/L123A double mutations [8,12]. Using molecular docking and molecular dynamics simulation, we target the interface of HBX-BLC-XL to curtail the role of this complex in infection
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