Insights on In Silico Approaches for Identifying Potential Allosteric Modulators From the Essential Oil of Pelargonium graveolens for TNF‐α in the Management of Rheumatoid Arthritis

ABSTRACT Tumor necrosis factor‐alpha (TNF‐α) is a key cytokine in inflammatory and autoimmune diseases, yet the lack of effective oral small‐molecule TNF‐α inhibitors necessitates alternative therapeutic approaches. This study employs in silico techniques to identify novel TNF‐α inhibitors from Pelargonium graveolens essential oil (PGEO). The chemical composition of PEGO was analyzed using GC‐MS, resulting in a library of 92 phytocompounds. Molecular docking studies were conducted to screen these compounds against the allosteric site of TNF‐α. Drug‐likeness analysis identified three promising candidates: Geranyl stearate, 1,4,7‐cycloundecatriene, 1,5,9,9‐tetramethyl‐, Z,Z,Z‐, and aristolene. The lead compounds were investigated using steered molecular dynamics (SMD) simulation, followed by molecular dynamics (MD) simulation for 200 ns. The binding affinity of the most promising compound was further evaluated using Molecular Mechanics Poisson–Boltzmann Surface Area (MMPBSA) calculations. The selected compounds exhibited stable interactions within the active pocket of TNF‐α. Geranyl stearate demonstrated the highest binding affinity (−75.03 kcal/mol), whereas the protein–protein interaction showed a weaker binding free energy (75.11 kcal/mol). The identified phytocompounds, particularly geranyl stearate, hold promise as TNF‐α inhibitors. Their stability and strong binding affinity support further investigation for the development of novel therapeutics targeting TNF‐α‐mediated autoimmune disorders.