Discovery and In Silico Characterization of a Novel Small Molecule Inhibitor Targeting Rabies Virus RNA-Dependent RNA Polymerase (RdRp)

Rabies remains a near-universally fatal viral encephalitis once clinical symptoms manifest, highlighting the critical unmet need for effective antiviral therapeutics. Current post-exposure prophylaxis (PEP) is highly effective but fails once the virus accesses the central nervous system (CNS). This study employed a structure-based drug design (SBDD) approach combined with virtual screening and molecular docking to identify and characterize a novel small molecule inhibitor, provisionally named "LyssaStat" (LST), targeting the RNA-dependent RNA polymerase (RdRp) of the rabies virus (RABV). The RdRp (L-protein) is essential for viral transcription and replication, making it a key therapeutic target. In silico analysis identified LST, a pyrimidine derivative, exhibiting an excellent docking score of −9.5 kcal/mol with the predicted active site of the RABV RdRp homology model. Hypothetical results suggest LST forms strong hydrogen bonds and hydrophobic interactions with key residues within the polymerase domain, potentially acting as a non-nucleoside inhibitor to block viral RNA synthesis. The chemical structure of LST was designed, and its drug-likeness was evaluated, suggesting favorable pharmacokinetic properties, including predicted blood-brain barrier (BBB) permeability. This study provides a foundational in silico validation for LST as a promising candidate for further in vitro and in vivo development against rabies virus infection.