Integrated in silico approach identifies Chrysosplenol D from Artemisia annua as a potent candidate against SARS-CoV-2, MERS-CoV, and HSV-2 proteases

Artemisia annua is well known for its antimalarial properties; however, its diverse phytochemicals have also attracted attention for their antiviral potential. In this study, an integrated in silico approach—combining molecular docking, ADMET profiling, and 200-ns molecular dynamics (MD) simulations coupled with MM/GBSA free-energy calculations—was applied to evaluate A. annua–derived compounds against the proteases of HSV-2, MERS-CoV, and SARS-CoV-2. Among the screened metabolites, Chrysosplenol D (Mol007395) was identified as a promising candidate based on a combined assessment of docking performance, favorable drug-likeness (full compliance with Lipinski’s rule of five), and the highest quantitative estimate of drug-likeness (QED = 0.608). While PASS predictions suggested potential antiviral activity, these results were considered supportive and remain computational in nature. MD simulations and MM/GBSA analyses demonstrated that Chrysosplenol D forms a strong and dynamically stable complex with the HSV-2 protease, driven primarily by favorable van der Waals and electrostatic interactions. In contrast, its interaction with the MERS-CoV 3CLpro was characterized by a more flexible yet moderately stable binding mode, whereas the SARS-CoV-2 protease complex exhibited weak and unstable binding behavior. Overall, these findings highlight Chrysosplenol D as a selective and energetically favorable in silico inhibitor of the HSV-2 protease, supporting its potential as a lead scaffold for further experimental validation and structure–activity optimization toward the development of anti-HSV-2 antiviral agents. The natural plant compound Chrysosplenol D was identified as a promising inhibitor of the HSV-2 protease (UL26). MD and MM/GBSA analyses revealed strong and stable binding to the HSV-2 protease, whereas interaction with MERS-CoV 3CLpro was energetically favorable but characterized by increased conformational flexibility. The results indicate selective in silico inhibition of the HSV-2 protease, with secondary and less stable activity against MERS-CoV 3CLpro. These findings provide a foundation for future experimental validation and anti-HSV-2–focused development of plant-derived antiviral agents.