Ameliorative Effects of Tetracarpidium conophorum (African Walnut) on Mercury-Induced Pancreatic Dysfunction: A Toxicological, Molecular Docking and Pharmacokinetic Study

Abstract

Mercury-induced pancreatic dysfunction is primarily driven by oxidative stress, inflammatory signaling, and metabolic dysregulation, underscoring the need for multi-target therapeutic candidates from natural sources. This study evaluated the therapeutic potential of bioactive compounds from Tetracarpidium conophorum (African walnut) using a combined in silico workflow involving molecular docking, pharmacokinetic profiling, and toxicity prediction. A total of seven key protein targets associated with pancreatic function, oxidative stress, inflammation, apoptosis, insulin resistance, lipid metabolism, and glucose regulation were analyzed. The highest binding affinity for the pancreatic function target (PDB: 1V4S) was observed with [2-(2-benzoylphenyl)-4-(1-hydroxycyclohexyl)phenyl]-[4-(1-hydroxycyclohexyl)phenyl]methanone (–8.4 kcal/mol). For the oxidative stress target (PDB: 1DGB), 7-chloro-10-hydroxy-1-(2-pyrrolidin-1-ylethylimino)-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-2H-acridin-9-one exhibited the strongest binding affinity (–11.5 kcal/mol), indicating strong potential interaction with redox-regulatory proteins. Across the evaluated targets, several ligands demonstrated comparable or improved binding affinities relative to standard reference compounds, including metformin, sitagliptin, butylated hydroxytoluene, and ascorbic acid, suggesting broad-spectrum inhibitory potential against key pathological pathways. ADME profiling indicated generally favorable gastrointestinal absorption, moderate-to-high plasma protein binding (>90%), and acceptable oral bioavailability for selected compounds, although variability in absorption and distribution parameters was observed across the dataset. Toxicity predictions suggested low risks of mutagenicity, carcinogenicity, and organ-specific toxicity for most lead compounds, supporting a favorable preliminary safety profile. Drug-likeness evaluation further indicated that several compounds complied with Lipinski, Veber, and Egan rules, suggesting acceptable oral drug-like properties. Overall, the results suggest that T. conophorum phytoconstituents may exert multi-target modulatory effects on pathways implicated in mercury-induced pancreatic injury. However, these findings remain computational in nature and require further validation through molecular dynamics simulations and in vivo experimental studies to confirm pharmacological efficacy and safety prior to clinical translation.