Theoretical visualization of covalent and non-covalent interactions: molecular diversity and substituent effects governing the reactivity of Bulbophyllum bibenzyl derivatives.

Natural products from Bulbophyllum species were systematically investigated as potential antioxidant scaffolds using density functional theory, real-space topological analyses, pharmacokinetic and toxicity prediction, molecular docking, and 100 ns molecular dynamics simulations, in comparison with Quercetin and Resveratrol. Frontier molecular orbital analysis revealed relatively large HOMO-LUMO gaps for the derivatives (5.41-5.67 eV) compared to 3.97 eV for the reference compounds, indicating higher electronic stability. Muscatilin displayed the lowest hardness (2.70 eV) and highest softness (0.185 eV-1), suggesting enhanced chemical reactivity. Real-space topological analyses (QTAIM, RDG/NCI, IRI, DORI, LOL, ELF) provide a molecular-level interpretation of interactions relevant to antioxidant behavior. In particular, Muscatilin exhibited a more favorable electron density distribution that may facilitate radical stabilization following hydrogen or electron transfer, thereby suggesting improved antioxidant potential. SwissADME profiling predicted favorable drug-likeness, high gastrointestinal absorption, and blood-brain barrier permeability for all compounds except Quercetin, while toxicity prediction showed high LD50 values for Tristin, Muscatilin, and Gigantol (2260 mg/kg) with nephrotoxicity as a shared class and improved cardiac safety for Muscatilin and Gigantol. Molecular docking results suggested binding affinities ranging from - 7.2 to - 9.2 kcal/mol toward bovine superoxide dismutase (SOD), with Muscatilin showing the most favorable interaction. Molecular dynamics simulations further indicated stable ligand binding within the SOD active channel, supported by MM-GBSA binding energy estimates. Collectively, Muscatilin and Gigantol are predicted to exhibit promising activity-safety profiles and may serve as potential antioxidant lead compounds, warranting further experimental validation.