Computer-aided drug repurposing & discovery for Hepatitis B capsid protein.

Abstract

The primary objective of this study is to harness computer-aided drug repurposing (CADR) techniques to identify existing FDA-approved drugs that can potentially disrupt the assembly of the Hepatitis B Virus (HBV) core protein (HBcAg), an essential process in the virus's life cycle. By targeting this critical step, our study aims to expand the repertoire of therapeutic options for managing chronic Hepatitis B infection, a major global health challenge. Utilizing a combination of computational methods, including the CavityPlus server for ability to analyze druggable protein cavities and extract pharmacophore features and LigandScout for pharmacophore-based virtual screening of a vast library of FDA-approved drugs was conducted. Molecular dynamic simulation (MDS) was employed to evaluate the stability of HBcAg, complexed with Heteroaryldihydropyrimidine (HAP) and statins exhibiting particularly strong binding energies and conformational compatibility. Our approach focused on identifying pharmacophore features that align with known HBcAg inhibitors. The study identified several promising candidates, including Ciclopirox olamine, Voriconazole, Enasidenib, and statins, demonstrating potential interactions with HBc protein residues. Molecular docking further validated these interactions. The significance of these findings lies in their potential to offer new, effective therapeutic strategies for HBV treatment, particularly as alternatives to current therapies that often suffer from issues of viral resistance and adverse side effects. MDS analysis verified the robustness of HAP and statins by showing a high level of binding energies and compatibility with HBcAg. Our results provide a foundation for further experimental validation and underscore the utility of computer-aided drug repurposing as a rapid, cost-effective approach to drug discovery in antiviral research. This study contributes to our understanding of HBV biology and opens avenues for developing novel anti-HBV therapies based on repurposed drugs. The highlighted compound may also enhance the challenges of drug resistance when used as a combination therapy.