Computational investigation of dioxin-like compounds as human sex hormone-binding globulin inhibitors: DFT calculations, docking study and molecular dynamics simulations

Abstract

Polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) are omnipresent and persistent environmental pollutants. In particular, 29 congeners are of special concern, and these are usually referred to as dioxin-like compounds (DLCs). Sex hormone binding globulin (SHBG) is a circulatory protein that binds sex steroids and is a potential target for endocrine disruptors in the human body. Herein, we report the optimization of DLCs employing density functional theory (DFT) to elucidate their frontier molecular orbitals and also the reactivity descriptors. The DFT outcome revealed that PCDFs and PCBs show the high dipole moment as well as high electrophilicity index and basicity. To assess the structure based inhibitory action of DLCs, these were docked into the active site cavity of hSHBG. Docking results show that the binding affinities of DLCs lie in the comparable range (−7.19 kca/mol to −9.12 kcal/mol) with Dihydrotestosterone (−10.94 kcal/mol), a substrate analogue of hSHBG. DLCs interact with the key residues such as Ser42, Asp65 and Asn82 and lie within the active site of hSHBG. Dynamics and stability of the DLCs-hACMSD complexes were determined by performing molecular dynamics simulations using GROMACS 5.1.1. The results emphasize that DLCs can structurally mimic the binding pattern of DHT to hSHBG, which further leads to inhibition of its activity.