Identification of potent antiviral from the fungal metabolites against SARS COV -۲ RdRp: An in silico study

Antiviral drugs target viral polymerases and are responsible for regulating viral replication. It is their selectivity that also allows the development of selective inhibitors, which, for example, may as much interfere with viral replication while causing minimum derogation to host cellular functions. This study investigated the antiviral potential of ۱۷۴ fungal secondary metabolites from the order Sordariales, specifically on their ability to inhibit the SARS-CoV-۲ RNA-dependent RNA polymerase (RdRp), an aspartyl polymerase. Following the blind docking step, which found ۵۶ ligands attached to the active site, the target docking revealed that ۱۰ ligands had binding energy < -۷ kcal/mol. This was the first step in the two-part virtual screening process. In the second step, ligands ۱-۳ showed the highest binding energy to the active site. The reference ligand (ribavirin) has lower binding affinities than ligands ۱-۳. In Lig-۳, the strongest interaction was seen. These are connected with important catalytic motifs through hydrophobic and hydrogen bonding interactions, which may prevent polymerase activity and hinder viral propagation. The impact of these ligands on polymerase dynamics and structure was then examined using ۱۰۰ nanosecond (ns) Molecular dynamic (MD) simulations. Lig-۱ and Lig-۳ caused further structural compressions in SARS-CoV-۲ that might destabilize the enzyme. Overall, Lig-۳ exerted the most conspicuous impact on polymerase, holding a higher potential for viral replication inhibition than Ribavirin. Lig-۳ is a promising antiviral candidate against SARS-CoV-۲ RdRp and merits more preclinical investigation due to its favorable ADME/T profile. The enhancement of the pharmacological properties of these candidates will require a combination of in silico modeling with experimental validation. Lig-۳ will be going from bench to bedside, with deep understanding fostered by continuous studies in structural biology, to become a great candidate against SARS-CoV-۲ and other viral menaces.

کلیدواژه ها:

COVID-۱۹ ، fungal secondary metabolite ، protein structure ، molecular modeling