Molecular docking and simulation analysis for elucidation of toxic effects of dicyclohexyl phthalate (DCHP) in glucocorticoid receptor-mediated adipogenesis

Abstract

ABSTRACT‘Obesogens’ are chemical agents that improperly regulate the genes involved in glucose metabolism and adipocyte differentiation and promote lipid accumulation and adipogenesis. The human glucocorticoid receptor (hGR) is a steroid hormone triggered transcriptional factor and regulates target genes important in basal glucose homeostasis. Molecular docking analysis was performed in order to assess in-silico structure based toxic effects of high molecular weight phthalates dicyclohexyl phthalate (DCHP) and its monophthalate metabolite mono-cyclohexyl phthalate (MCHP). Molecular docking results show that the binding affinities of DCHP and MCHP lie in the comparable range (−7.87 kcal/mol and −6.24 kcal/mol) with Dexamethasone (−10.2 kcal/mol), a potent agonist for hGR. These two PAEs occupy the active site of hGR and interact with the key residues. Molecular simulation results infer that hGR-PAEs complexes were stable. Density functional theory (DFT) analysis indicates that HOMO and LUMO energy gap of DCHP (3.88 eV) and MCHP (3.39 eV) are comparable to DEX (4.69 eV). Binding free energy calculations of the DCHP-hGR and MCHP-hGR complexes were estimated by using Molecular Mechanic/Poisson-Boltzmann Surface Area (MMPBSA) method. Molecular Docking and simulation results emphasise that DCHP and MCHP can efficiently bind to hGR, which further leads to glucocorticoid-mediated adipogenesis in a synergistic manner.