In silico drug repurposing of potential antiviral inhibitors targeting methyltransferase (2'-O-MTase) domain of Marburg virus.

Marburg Virus (MARV) presents a significant threat to human health, highlighting the urgent need for effective therapeutics. The MARV genome encodes a multifunctional 'large' L protein that plays a crucial role in polymerase, capping, and methyltransferase activities. Within this protein, the 2'-O-methyltransferase (2'-O-MTase) domain is essential for viral replication and immune evasion, making it a promising therapeutic target. However, the lack of structural data on this domain limits drug discovery efforts. To address this challenge, we utilized AlphaFold2 to predict a 3D structure of the MARV 2'-O-MTase domain. Molecular docking with its natural ligand, S-adenosyl methionine (SAM), allowed us to identify key active-site residues involved in ligand binding. We then screened 62 known inhibitors against this domain and identified four promising candidates: Lifirafenib (- 9.5 kcal/mol), Dolutegravir (- 8.5 kcal/mol), BRD3969 (- 8.3 kcal/mol), and JFD00244 (- 8.2 kcal/mol). Further, we assessed the pharmacokinetic and pharmacodynamic properties of these compounds to evaluate their drug-likeness. Molecular dynamics simulations, along with MM/GBSA free energy calculations, confirmed stable interactions between the selected inhibitors and the target domain. While these findings highlight promising candidates for MARV, experimental validation through in vitro and in vivo assays is essential to assess their safety and efficacy. Graphical abstract: Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-025-00355-z.