In Silico Drug Design Targeting the Rabies Virus Glycoprotein: Phytochemicals as Promising Drug Candidates

ABSTRACT Rabies is an RNA virus with a single‐stranded, negative‐sense genome and is classified under the Lyssavirus genus. It is estimated that the rabies virus (RABV) causes approximately 59,000 deaths worldwide each year. Although effective vaccines are available to prevent rabies, recent literature reviews indicate a lack of specific antiviral medications or therapeutic agents for treating rabies infections. In this study, we targeted the RABV glycoprotein (G) to design a potential therapeutic agent using computational de novo drug discovery approaches. A set of randomly selected antiviral phytochemicals was screened against the G (PDB ID: 6TOU). Structural validation of the target protein was confirmed via Ramachandran plot analysis, which showed 88% of residues in favored regions. Among the 36 active compounds evaluated through molecular docking, morusinol emerged as the top candidate, exhibiting the lowest binding energy of −8.0 kcal/mol. Additionally, it demonstrated favorable drug‐like properties, including a bioavailability score of 0.55, water solubility of −3.19, and a synthetic accessibility score of 6.61. Toxicity predictions indicated that morusinol is considered nontoxic, showing no signs of acute toxicity through inhalation or dermal exposure, and it does not cause eye or skin irritation or corrosion. Furthermore, morusinol complies with the Lipinski rule of five, supporting its drug‐likeness. A 100‐ns molecular dynamics simulation of the Morusinol–6TOU complex revealed stable binding interactions throughout the simulation period, further validating its potential as a candidate drug for treating RABV infections.