Structure-Guided Approach to Identify Potential Inhibitors of Large Envelope Protein to Prevent Hepatitis B Virus Infection

Abstract

Hepatitis B virus (HBV) infection is one of the major causes of liver diseases, which can lead to hepatocellular carcinoma. The role of HBV envelope proteins is crucial in viral morphogenesis, infection, and propagation. Thus, blocking the pleiotropic functions of these proteins especially the PreS1 and PreS2 domains of the large surface protein (LHBs) is a promising strategy for designing efficient antivirals against HBV infection. Unfortunately, the structure of the LHBs protein has not been elucidated yet, and it seems that any structure-based drug discovery is critically dependent on this. To find effective inhibitors of LHBs, we have modeled and validated its three-dimensional structure and subsequently performed a virtual high-throughput screening against the ZINC database using RASPD and ParDOCK tools. We have identified four compounds, ZINC11882026, ZINC19741044, ZINC00653293, and ZINC15000762, showing appreciable binding affinity with the LHBs protein. The drug likeness was further validated using ADME screening and toxicity analysis. Interestingly, three of the four compounds showed the formation of hydrogen bonds with amino acid residues lying in the capsid binding region of the PreS1 domain of LHBs, suggesting the possibility of inhibiting the viral assembly and maturation process. The identification of potential lead molecules will help to discover more potent inhibitors with significant antiviral activities.

Identification of Potential HCV Inhibitors Based on the Interaction of Epigallocatechin-3-Gallate with Viral Envelope Proteins

“…In one of the current studies, computational docking reveals the set of 23 drugs that block the viral infection on CD-81 binding site, but after experimental analysis only one ligand was capable of binding to inhibit the infection of Huh-7 cells. While the binding energy of the drugs ranges from −8.64 to −6.36 [ 52 ], the binding energy of the drugs obtained from our virtual screening ranges from −13.2 to −11.…”

“…Some previous studies [ 51 ] show hydrogen and other interactions of sofosbuvir and ribavirin with HCV envelope protein during docking studies. Similarly, in other studies [ 52 ], the envelope protein is targeted for identification of various inhibitory molecules. In total, ZINC11882026, ZINC19741044, ZINC00653293, and ZINC15000762 are identified as potential candidates and recognized as appreciable drugs for viral envelope protein.…”

Mapping the conformational epitope of a therapeutic monoclonal antibody against HBsAg by in vivo selection of HBV escape variants

“…Bioinformatic analysis was used to predict the HBsAg structure in our study. [ 15 ] The genotype D HBsAg aa sequence was submitted to the I‐TASSER server, which uses solved protein structures as templates to generate three‐dimensional atomic models. [ 16 ] The simulation acquired from I‐TASSER was further checked for its average and stereochemical quality by the ProTSAV and MolProbity platforms.…”