Fungal benzophenone derivatives as antiviral inhibitors of Vaccinia thymidylate kinase: An integrated docking, dynamics, and ADMET study
Azizah M. Malebari, Abdelsattar M. Omar, Khaled M. Elamin, Gamal Abdallah Mohamed, Sabrin R. M. Ibrahim · Letters in Drug Design & Discovery · 2025
Natural products are one of the underexplored sources of novel antivirals, particularly polyphenolic compounds produced by plants and fungi. Benzophenones represent a diverse class of polyphenols that have shown a broad spectrum of bioactivities. This study presented a computational screening of five fungal benzophenone derivatives – 3-de-O-methylsulochrin ( 1 ), monodictyphenone ( 2 ), arugosin H ( 3 ), arugosin I ( 4 ), and arugosin A ( 5 ) as potential inhibitors of Vaccinia virus thymidylate kinase (vTMPK) in comparison to the native substrate, thymidine diphosphate (TDP). A multi-faceted in silico approach was employed, including Glide extra-precision (XP) molecular docking, Prime MM-GBSA binding free energy calculations, induced-fit docking, 100-ns molecular dynamics (MD) simulations, and ADMET property predictions. All five analogues were found to bind in the TDP pocket with favorable geometries, achieving XP docking scores in the range of approximately –8.3 to –6.4. Although none surpassed the native ligand (XP GScore –13.5), the top-performing candidate (compound 4 ) achieved a docking score (–8.2) near the top of this range. Consistently, compound 4 showed the most favorable MM-GBSA binding energy (ΔG bind ≈ –61.7 kcal/mol) among the analogues, approaching TDP’s binding energetics (–67.6 kcal/mol). MD simulations confirmed that the compound 4–vTMPK complex was highly stable, with minimal backbone and ligand RMSD fluctuations (∼1.3 Å and ∼1.0 Å, respectively) comparable to the native TDP–enzyme complex. ADMET predictions further highlighted compound 4’s drug-like profile: it was orally bioavailable (∼94 % human absorption), moderately lipophilic (QPlog P o/w ∼3.9), and had only a borderline hERG liability – a marked improvement over the polar TDP substrate. Taken together, these results identified compound 4 as a promising lead candidate that combine potent target engagement with favorable pharmacokinetic and safety characteristics for antiviral development. This study highlights the potential of fungi-derived secondary metabolites as sustainable sources of drug discovery and advances biomedical innovation through computational drug design that contributes to the global effort against viral threats.