Valorization of a Natural Compound Library in Exploring Potential Marburg Virus VP35 Cofactor Inhibitors via an In Silico Drug Discovery Strategy.

This study focuses on exploring potential inhibitors of the Marburg virus interferon inhibitory domain protein (MARV-VP35), which is responsible for immune evasion and immunosuppression during viral manifestation. A combination of in silico techniques was applied, including structure-based pharmacophore virtual screening, molecular docking, absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis, molecular dynamics (MD), and molecular stability assessment of the identified hits. The docking scores of the 14 selected ligands ranged between -6.88 kcal/mol and -5.28 kcal/mol, the latter being comparable to the control ligand. ADMET and drug likeness evaluation identified Mol_01 and Mol_09 as the most promising candidates, both demonstrating good predicted antiviral activity against viral targets. Density functional theory (DFT) calculations, along with relevant quantum chemical descriptors, correlated well with the docking score hierarchy, and molecular electrostatic potential (MEP) mapping confirmed favorable electronic distributions supporting the docking orientation. Molecular dynamics simulations further validated complex stability, with consistent root mean square deviation (RMSD), root mean square fluctuation (RMSF), and secondary structure element (SSE) profiles. These findings support Mol_01 and Mol_09 as viable candidates for experimental validation.