Computational screening of natural compounds reveals glycyrrhisoflavone as a potential Hepatitis B X-interacting protein inhibitor.

BACKGROUND AND

OBJECTIVE

Hepatitis B virus (HBV) remains a major global health burden, affecting ∼296 million people worldwide. Chronic infection can progress to liver cirrhosis and hepatocellular carcinoma (HCC), partly due to viral persistence mechanisms that current antivirals do not fully address, including the failure to eliminate covalently closed circular DNA (cccDNA) and the emergence of drug resistance. Hepatitis B X-interacting protein (HBXIP) is a key host factor that supports HBV persistence and promotes oncogenic processes, making it an attractive therapeutic target.

METHODS

This study investigated natural phytochemicals as potential inhibitors of HBXIP using an integrated computational pipeline. A library of 343 ethnobotanically sourced phytochemicals was curated and filtered using ADMET profiling to prioritize compounds with favorable pharmacokinetic and toxicity profiles. To validate complex stability, 200 ns molecular dynamics simulations were performed.

RESULTS

The shortlisted compounds were docked against HBXIP (PDB ID: 3MSH), identifying glycyrrhisoflavone, diosmetin, lignans, and luteolin as leading candidates. Glycyrrhisoflavone showed the strongest binding affinity and formed stable interactions within the HBXIP active site. Glycyrrhisoflavone displayed minimal protein-ligand fluctuations, indicating a stable complex, whereas Luteolin showed greater flexibility that may enable adaptive binding but could reduce interaction stability. RMSD, RMSF, and SASA analyses supported these observations, with glycyrrhisoflavone exhibiting the most favorable overall dynamics.

CONCLUSIONS

Glycyrrhisoflavone and lignans emerge as promising natural leads for HBXIP-targeted therapies, potentially complementing existing antivirals with lower side-effect potential. The integration of multi-level computational analyses highlights the novelty of this study and supports glycyrrhisoflavone as a promising HBXIP-targeting phytochemical lead for future experimental validation.