Interaction dynamics of boswellic acid analogs with TNFR1 and TNFR2: a molecular docking and simulation study

Tumor necrosis factor receptors (TNFR1 and TNFR2) play important roles in inflammatory and immune signaling and are associated with several inflammatory and autoimmune diseases. Despite the reported anti-inflammatory activity of boswellic acid, less is known about the interactions of structurally related analogs with TNFR1 and TNFR2. In this study, boswellic acid and structurally related analogs were evaluated computationally against TNFR1 and TNFR2, with the interaction profiles assessed separately for each receptor subtype. Based on the overall computational results, paeonenoide B (B3) and paeonenoide C (B4) were selected for further investigation. Molecular dynamics simulations and MM-GBSA calculations indicated that both compounds remained associated with the receptors throughout the simulations, although differences in interaction patterns and conformational behavior were observed between the TNFR1 and TNFR2 systems. These findings may be useful for future experimental evaluation of boswellic acid-related compounds.

Boswellic acid-like compounds were identified by structural similarity searching in PubChem and evaluated using drug-likeness and ADME/T analyses performed with ADMETlab 2.0. Molecular docking was carried out against TNFR1 (PDB ID: 1EXT) and TNFR2 (PDB ID: 3ALQ) using UCSF Chimera and AutoDock Vina. Selected complexes were subjected to molecular dynamics simulations following ligand parameterization with Gaussian 16 and AmberTools16. Three independent 500-ns simulations were performed for each system in explicit solvent. Structural analyses were performed using CPPTRAJ and PyMOL, and binding free energies were estimated using the MM-GBSA method.