Computational Screening and Prioritization of Bridged Heterocycle Compounds Against SARS-CoV-2 RNA-Dependent RNA Polymerase (RdRp)

SARS-CoV-2, the etiological agent of coronavirus disease 2019 (COVID-19), has inflicted an unprecedented global health crisis, claiming over seven million lives worldwide as reported by the World Health Organization (WHO). Despite the deployment of efficacious vaccines, the relentless emergence of immune-evasive variants and the limited breadth of existing antiviral arsenals underscore the critical imperative to discover mechanistically novel therapeutic agents. The RNA-dependent RNA polymerase (RdRp; nsp12), a catalytic cornerstone of the viral replication-transcription complex, represents an evolutionarily conserved and pharmaceutically tractable target. In the present investigation, a structure-guided blind molecular docking workflow was implemented within the SeeSAR 13.1 platform to evaluate a library of chemically synthesized bridged heterocyclic scaffolds as potential RdRp-targeting candidates. Comprehensive pharmacokinetic profiling was conducted to assess drug-likeness. Among all candidates, compound 1e emerged as the top-ranked hit, exhibiting the highest docking scores (−12.68 and −17.38 in the absence and presence of mRNA, respectively) and favourable contacts with conserved template-interacting region residues (Motifs F and G). Subsequent all-atom molecular dynamics (MD) simulations over 100 ns demonstrated conformational stability of both the 1e-RdRp and 1e-RdRp-mRNA ternary complexes throughout the 100 ns simulated trajectory. The computational evidence suggests the predictive binding to the template-interacting region, which necessitates experimental validation for mechanistic confirmation. Collectively, these findings identify compound 1e as a prioritized computational hit and lead RdRp antagonist, warranting rigorous in vitro RdRp inhibition assays, cell-based antiviral evaluations, and full pharmacological validation before any antiviral claim can be made.