Integrated computational approach revealed the potential inhibitory effect of xanthone derivatives against Marburg virus nucleocapsid.

The Marburg virus (MARV), a member of the Filoviridae family, poses a severe threat to global health due to its high mortality rate and lack of effective therapeutics. In this study, Xanthone derivatives from Swertia chirata were investigated for their potential to inhibit the VP35 RNA-binding domain of MARV using a structure-based virtual screening approach. Molecular docking revealed that Magniferin showed the highest binding affinity (-7.0 kcal/mol) among the selected phytocompounds, outperforming the reference drug Remdesivir (-5.0 kcal/mol). All compounds complied with Lipinski's Rule of Five and exhibited favorable ADME and toxicity profiles. Molecular dynamics (MD) simulations over 100 ns confirmed the stability of the Magniferin-VP35 complex through post dynamic analysis and interaction analysis. Furthermore, Principal Component Analysis (PCA) and Free Energy Landscape (FEL) mapping indicated that the complex resided in multiple low-energy conformational states, supporting its thermodynamic stability and conformational flexibility. The Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) analysis indicated a strong binding affinity with key contributions from Vander Waals and Coulombic interactions. These findings suggest that Magniferin could serve as a promising lead compound for the development of MARV therapeutics. Supplementary Information: The online version contains supplementary material available at 10.1007/s13337-025-00933-x.