In-Silico Screening of T3DB-Derived Compounds as Putative Marburg Virus VP35 Inhibitors: Docking, Molecular Dynamics, MM/GBSA, ADMET, and DFT Analyses

Background Marburg virus (MARV) ranks among the most detrimental zoonotic viruses, exhibiting lethal impacts on nonhuman and human primates. Owing to recurring MARV outbreaks marked by a high mortality rate, the WHO classified it as a risk group 4 pathogen and underscored the imperative demand for developing viable medications. Among the potential viral targets, the polymerase cofactor (VP35) serves as a promising target due to its central function in the replication process. The purpose of this study was to identify potential VP35 inhibitors from toxicological sources using computational approaches. Methods In-silico computations were performed to identify VP35 inhibitors derived from toxicological sources. The T3DB database was screened to identify potent inhibitors against VP35 through docking estimations. The top-scoring toxins were further characterized using molecular dynamics simulations (MDS) and MM/GBSA binding energy computations. Results Following 300 ns MDS with MM/GBSA analysis, two toxins —namely T3D4864 and T3D3233— demonstrated more favorable binding affinities toward VP35 with Δ G binding values of −42.0 and −37.9 kcal/mol, respectively, in comparison with galidesivir (Δ G binding = −16.3 kcal/mol). Their superior binding was attributed to multiple H-bonds, hydrophobic, and vdW interactions with the key residues of VP35. Post-MD structural and energetic analyses, including radius of gyration and root-mean-square deviation analyses, confirmed the stability of the identified toxins bound to VP35 over 300 ns MDS. Subsequently, DFT computations were performed to evaluate the electronic features of the identified toxins, revealing their favorable chemical reactivities. Conclusion These computational findings suggest that T3D4864 and T3D3233 may represent putative VP35 inhibitors for further investigation. However, this study is limited to in-silico predictions and necessitates further experimental validation of antiviral activity, cytotoxicity, selectivity, and pharmacological safety. Funding This work was funded by Ongoing Research Funding Program (ORF-2026-759), King Saud University, Riyadh, Saudi Arabia.