Design and <i>in-silico</i> evaluation of PNA-based novel pronucleotide analogues targeting RNA-dependent RNA polymerase to combat COVID-19

The emergence of highly contagious SARS-CoV-2 variants emphasizes the need for antiviral drugs that can adapt to evolving viral mutations. Despite widespread vaccination efforts, novel variants and recurrence cases raise concerns about COVID-19. Although repurposed drugs like Remdesivir, a nucleoside inhibitor, offer treatment, there is still a critical need for alternative drugs. Inhibiting viral RdRp function remains a key strategy. Structural analysis highlights the importance of pyrrolo-triazine and pyrimidine scaffolds in nucleoside inhibitors. Our study designed Peptide Nucleic Acid (PNA) antisense pronucleotides by combining these scaffolds using structure-guided drug design. Molecular modeling, including molecular docking, pharmacokinetics, molecular dynamics simulations, and MMPBSA binding energy calculations, predicts that modified PNAs can disrupt ribosome assembly at the RdRp translation start site. The neutral backbone of PNAs may enhance sequence-specific RNA binding. MD simulations revealed that complexes of Remdesivir and L14 remained stable throughout, with the phosphate tail of L14 stabilized by a positive amino acid pocket near the RdRp-RNA entry channel, similar to Remdesivir. Additionally, L14's guanine motif interacted with U20, A19, and U18 on the primer RNA strand. The lead PNA analog (L14) showed superior binding free energy to both RdRp (−47.26 kcal/mol) and RdRp-RNA (−85.66 kcal/mol), outperforming Remdesivir. Key amino acid residues critical for binding affinity were identified, providing valuable insights for drug development. This promising PNA-mimetic compound offers dual-target specificity, presenting a compelling avenue for developing potent anti-SARS-CoV-2 agents. This article provides the rational design of peptide nucleic acid (PNA) analogs as a potential medication for developing RdRp inhibitors to attenuate coronavirus illness 2019 (COVID-19).We designed PNA mimetics by adding stable PNA backbone and phosphinimidate group to increase the cellular permeability, while a methylene carbonyl linkage connects the nucleotide bases which are required for the RNA machinery using structure-guided drug design.The designed PNA analogs have a dual-target effect against RdRp protein active site and sequence-specific RdRp-RNA complex of SARS-CoV-2 to control viral replication.Molecular dynamics simulation, quantum chemical, and ADMET analysis could be used as additional resources for the new drug designing process.The rational development of the anti-coronavirus PNA lead molecule will enable researchers in this field to develop a new generation of RdRp inhibitors. This article provides the rational design of peptide nucleic acid (PNA) analogs as a potential medication for developing RdRp inhibitors to attenuate coronavirus illness 2019 (COVID-19). We designed PNA mimetics by adding stable PNA backbone and phosphinimidate group to increase the cellular permeability, while a methylene carbonyl linkage connects the nucleotide bases which are required for the RNA machinery using structure-guided drug design. The designed PNA analogs have a dual-target effect against RdRp protein active site and sequence-specific RdRp-RNA complex of SARS-CoV-2 to control viral replication. Molecular dynamics simulation, quantum chemical, and ADMET analysis could be used as additional resources for the new drug designing process. The rational development of the anti-coronavirus PNA lead molecule will enable researchers in this field to develop a new generation of RdRp inhibitors.