Antiviral Activity of Dopamine Geldanamycin Hybrids Against Influenza Virus and Association with Molecular Docking Analysis

摘要

Background and Objective: Geldanamycin (GDM) is an antibiotic isolated from Streptomyces zerumbet W14 that specifically targets and deactivates heat shock protein 90 (Hsp90) to inhibit virus replication. The therapeutic utilization of GDM has been restricted by its low water solubility and severe hepatotoxicity. The aim of the present study was to synthesis the novel geldanamycin derivatives and evaluate their biological properties. Materials and Methods: Five new Dopamine Geldanamycin Hybrids (DGH); compounds 2-6 were synthesized by nucleophilic substitution of GDM (1). Solubility, cytotoxicity, antiviral activity and molecular docking analyses were carried out. Results: The solubility of DGH in water was 0.386-5.464 mM, higher than that of compound 1. These compounds exhibited weak cytotoxic activity against LLC-MK2 and Vero cells, with IC 50 values in the range of 104.52-496.31 μg mL ?1 . These compounds (except compound 5) inhibited influenza virus propagation in embryonated chicken eggs at the minimum inhibitory concentration of 6.25 μg mL ?1 . They interacted positively with Hsp90, showing binding free energy (ΔG) of -100.50 to -114.28 kcal mol ?1 , which indicated lower Hsp90 affinity compared with that of geldanamycin (-141.296 kcal mol ?1 ) and 17-dimethylamino ethylamino-17-demethoxygeldanamycin (-145.307 kcal mol ?1 ), despite being partly bound in the active site (compounds 2, 3 and 6) or outside the active site (compound 4). Conclusion: The study findings revealed, through molecular docking analysis, that the development of DGH improved the pharmacokinetic profiles of solubility, cytotoxicity and antiviral activities. It is, therefore, recommended DGH that is a potential alternative treatment agent for influenza virus infection.