همایش ملی بیوانفورماتیک ایران

صفحه اصلی / 4th international edition and 13th Iranian Conference on Bioinformatics

Investigation of antiviral potency of fungal metabolites against Hepatitis C NS5B

نویسندگان :

Zohreh Sahhaf Razavi¹ Ali Ramazani² Armin Zarei³

1- دانشگاه زنجان 2- دانشگاه زنجان 3- دانشگاه زنجان

کلمات کلیدی :

HCV NS5B Polymerase،Secondary metabolites،Protein structure،Molecular simulation

چکیده :

Viral polymerases are essential for viral replication and thus important targets for developing antiviral therapies. These enzymatic proteins facilitate the assembly of novel viral entities within the compromised host cells by catalyzing the synthesis of either viral RNA or DNA. These enzymes' unique mechanisms of action enable selective inhibition, which markedly contrasts with the functionalities of host polymerases. (Choi 2012, Peng, Wang et al. 2022)This investigation evaluated one hundred seventy-four secondary metabolites derived from the order Sordariales, which belongs to the phylum Ascomycota (Charria-Girón, Surup et al. 2022, Zhao, Wang et al. 2023), encompasses an extensive and diverse fungal group that produces secondary metabolites like terpenes, alkaloids, and polyketides and conducted screening against aspartyl polymerases, including Hepatitis C (HCV) NS5B.(Mosley, Edwards et al. 2012, Manns, Buti et al. 2017) by using a comprehensive two-step virtual screening approach, ten of the 56 identified ligands that demonstrated binding within the active sites of the polymerases under examination exhibited binding energies that were less than -7 kcal/mol. The reference compound, ribavirin, showed lower binding affinity than ligands 1-3. Ligand 3 demonstrated the most important interaction provided by hydrophobic and hydrogen bonds with key residues inside the catalytic active center. The results showed that this enzyme can block virus replication by inhibiting its function.(Ansari, Zarei et al. 2023) A 100 nanosecond (ns) molecular dynamics simulation was used to further study the effect of these ligands on the structural integrity and dynamic properties of the polymerase. (Lindahl, Hess et al. 2001, Schüttelkopf and Van Aalten 2004)The binding of ligands 2 and 3 led to significant structural changes that led to an increase in polymerase activity. The flexibility and operability of hepatitis C virus NS5B polymerase have been significantly reduced. Ligand 3 had the most significant effect on polymerase and exceeded the effectiveness of ribavirin in inhibiting viral replication. In addition, ligand 3 provides a good ADME/T profile, which confirms its potential as a promising candidate for activity against HCV NS5B and justifies further preclinical studies.