In silico molecular study of hepatitis B virus X protein as a therapeutic target

by Selleckchem | Oct 25 2023

The Hepatitis B virus is a leading cause of liver cirrhosis and hepatocellular carcinoma. HBx viral protein is considered a contributor to pathogenesis and hepatocarcinogenesis. This study aimed to screen the effect of some antiviral compounds to target HBx protein for inhibition of its function. Here, molecular docking, molcular dynsmic simulation, MM/GBSA and T-SNE methods were applied to study the complex stability and to cluster the conformations that generated in the simulation. Among the 179 compounds screened in this study, three antiviral agents (SC75741, Punicalagin, and Ledipasvir) exhibited the lowest docking energy and best interaction. Among these compounds, SC75741 was identified as a potent inhibitor of HBx that showed the best and most stable interaction during molecular dynamic simulation, and blocking a region near to HBx helix resides (aa 88-100) that is associated with cell invasion. The analysis of relative binding free energy through MM/GBSA for molecular dynamic simulation results revealed binding energy -9.9 kcal/mol for SC75741, -11 kcal/mol for Punicalagin, and -10.1 kcal/mol for Ledipasvir. These results elucidate the possible use of these compounds in the research for targeting HBx.

Comments:

The study aimed to investigate the potential of various antiviral compounds to target the HBx protein, which is known to contribute to the pathogenesis and development of hepatocellular carcinoma and liver cirrhosis caused by the Hepatitis B virus. The researchers employed several computational methods, including molecular docking, molecular dynamic simulation, MM/GBSA, and T-SNE, to assess the stability of the protein-compound complexes and cluster the conformations generated during the simulation.

Out of the 179 compounds screened, three antiviral agents, namely SC75741, Punicalagin, and Ledipasvir, demonstrated the lowest docking energy and exhibited the most favorable interactions with the HBx protein. Among these compounds, SC75741 emerged as a potent inhibitor of HBx, displaying the best and most stable interaction throughout the molecular dynamic simulation. It was observed to bind to a region near the HBx helix residues (amino acids 88-100), which are associated with cell invasion.

Further analysis using the MM/GBSA approach to estimate the relative binding free energy of the molecular dynamic simulation results revealed a binding energy of -9.9 kcal/mol for SC75741, -11 kcal/mol for Punicalagin, and -10.1 kcal/mol for Ledipasvir. These findings indicate that these compounds have a strong binding affinity for HBx and suggest their potential usefulness in future research focused on targeting HBx.

Overall, this study provides insights into the efficacy of these antiviral compounds in inhibiting the function of the HBx protein, highlighting their potential as therapeutic agents for combating the pathogenesis and hepatocarcinogenesis associated with the Hepatitis B virus.