A novel piperazine derivative that targets hepatitis B surface antigen effectively inhibits tenofovir resistant hepatitis B virus
| Autor: | Bhyravabhotla Jayaram, Ruchika Bhat, Perumal Vivekanandan, Anurag S. Rathore, S Kiruthika, Rozaleen Dash |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Models Molecular HBsAg medicine.disease_cause Virus Replication Virtual drug screening 01 natural sciences Piperazines Catalytic Domain Cytotoxicity Multidisciplinary 010304 chemical physics Chemistry Small molecules High-throughput screening virus diseases Genomics Hepatitis B Small molecule Medicine Protein Binding Hepatitis B virus Science Genome Viral Antiviral Agents Virus Article Target validation 03 medical and health sciences Structure-Activity Relationship Target identification 0103 physical sciences Drug Resistance Viral medicine Humans Tenofovir Binding Sites Hepatitis B Surface Antigens Dose-Response Relationship Drug medicine.disease Virology digestive system diseases 030104 developmental biology Docking (molecular) DNA Viral Nucleoside |
| Zdroj: | Scientific Reports Scientific Reports, Vol 11, Iss 1, Pp 1-13 (2021) |
| ISSN: | 2045-2322 2045-1377 |
| Popis: | Chronic hepatitis B virus (HBV) infection is a global problem. The loss of hepatitis B surface antigen (HBsAg) in serum is a therapeutic end point. Prolonged therapy with nucleoside/nucleotide analogues targeting the HBV-polymerase may lead to resistance and rarely results in the loss of HBsAg. Therefore, inhibitors targeting HBsAg may have potential therapeutic applications. Here, we used computational virtual screening, docking, and molecular dynamics simulations to identify potential small molecule inhibitors against HBsAg. After screening a million molecules from ZINC database, we identified small molecules with potential anti-HBV activity. Subsequently, cytotoxicity profiles and anti-HBV activities of these small molecules were tested using a widely used cell culture model for HBV. We identified a small molecule (ZINC20451377) which binds to HBsAg with high affinity, with a KD of 65.3 nM, as determined by Surface Plasmon Resonance spectroscopy. Notably, the small molecule inhibited HBsAg production and hepatitis B virion secretion (10 μM) at low micromolar concentrations and was also efficacious against a HBV quadruple mutant (CYEI mutant) resistant to tenofovir. We conclude that this small molecule exhibits strong anti-HBV properties and merits further testing. |
| Databáze: | OpenAIRE |
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