In silico insights into (±)-zanthonitidumine B: anti-Inflammatory potency and enantiomeric selectivity through molecular docking, DFT, and MEP studies

Inflammation becomes pathogenic when dysregulated, with interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) acting as central mediators. (±)-Zanthonitidumine B, a racemic benzophenanthridine alkaloid from Zanthoxylum nitidum , has been reported to suppress these cytokines. In this study, the enantiomers (+)-zanthonitidumine B and (–)-zanthonitidumine B were investigated using molecular docking supported by density functional theory (DFT) and molecular electrostatic potential (MEP) analyses. Docking simulations against TNF-α (PDB: 6X86; validated by redocking of the co-crystallized ligand, Δ G bind = –13.13 kcal/mol) revealed that (–)-zanthonitidumine B exhibited stronger (more negative) binding (Δ G bind = –10.73 kcal/mol) than (+)-zanthonitidumine B (Δ G bind = –8.68 kcal/mol), forming a hydrogen bond with Tyr:119 (2.61 Å) and multiple hydrophobic contacts. Against IL-6 (PDB: 1ALU), both enantiomers showed comparable affinities [(+): –7.76 kcal/mol; (–): –7.64 kcal/mol] but distinct binding modes— (+)-zanthonitidumine B interacting with Gln:127/Ile:136 and (–)-zanthonitidumine B with Asp:140 and π–σ contacts at Leu:147. DFT results indicated a smaller HOMO–LUMO gap for (–)-zanthonitidumine B (2.71 eV) compared to (+)-zanthonitidumine B (1.97 eV), while MEP maps highlighted electron-rich regions near oxygen atoms, rationalizing the observed interaction hot spots. Collectively, these in silico results nominate (–)-zanthonitidumine B as the stronger TNF-α binder and suggest comparable IL-6 engagement for both enantiomers, providing stereochemical hypotheses to guide future chiral isolation and in vitro anti-inflammatory validation. • (–)-Zanthonitidumine B binds TNF-α stronger than (+)-enantiomer. • Both enantiomers exhibit comparable binding affinity toward IL-6. • DFT/MEP analysis correlates electronic properties with selectivity. • (–)-Enantiomer displays lower HOMO–LUMO gap and higher reactivity. • Study supports rational design of chiral anti-inflammatory agents.