Abstract
Millions of lives have been lost to the deadly SARS-CoV-2 virus. Vaccines and antiviral drugs are essential scientific tools in combating viral infections. This in silico study focused on the RdRp inhibitor favipiravir, exploring new analogs by substituting the fluorine atom on the pyrazine ring with both homocyclic and heterocyclic moieties. Initially, ADME and toxicity properties were assessed using SwissADME and ProTox-II online tools. Ligands L6 and L7 exhibited high bioavailability and drug-likeness compared to favipiravir. Subsequently, all new analogs were docked into the RdRp active site using AutoDock Vina, demonstrating high affinity compared to favipiravir. Based on optimal ADMET profiles and docking scores, ligands L4, L6, and L7 underwent 200 ns MDS using the CHAARM 36 force field in NAMD software to validate docking results. Various trajectory analyses, including RMSD, RMSF, histograms, total number of contacts, and ligand properties, were conducted to gain insights into the interaction patterns between ligands and RdRp. All protein-ligand complexes exhibited greater stability than favipiravir throughout simulations period. This theoretical study suggests that ligands L6 and L7 could serve as lead candidates for RdRp inhibition. Cell-Based SARS-CoV-2 RdRp Activity Assay is recommended to validate these in silico findings.