Molecular insights into the promiscuous interaction of human pregnane X receptor (hPXR) with diverse environmental chemicals and drug compounds.

The nuclear receptor member human pregnane X receptor (hPXR) regulates enzymes and transporters involved in xenobiotic detoxification as well as maintains homeostatic balance of bile acids, thyroid and steroid hormones. hPXR can be recognized and activated by a structurally diverse array of environmental chemicals and drug compounds to initiate adverse biological effects, such as perturbing normal physiological functions and causing dangerous drug-drug interactions and exhibiting a high promiscuity in its ligand spectrum. Understanding of the molecular mechanism and biological implication underlying the promiscuous interaction of hPXR with its diverse ligands is fundamentally important for toxicological and pharmaceutical researches. In the current study, molecular docking and hybrid quantum mechanics/molecular mechanics (QM/MM) were employed to investigate the binding mode, structural basis and energetic property of hPXR interactions with various activators and non-activators. It was found that, as compared to non-activators, the activators adopt few dominant modes to tightly interact with hPXR, which are specified by few polar spots located on the hydrophobic surface of hPXR active pocket. Based on the findings, a novel method called multiple binding mode-based quantitative structure-activity relationship (MBMB-QSAR) that characterizes the nonbonded interaction profile of hPXR with its ligand in multiple binding modes was proposed to model and predict the activating potency of small-molecule compounds on hPXR. Several partial least square (PLS) predictors derived from the MBMB-QSAR modeling were demonstrated to be effective for quantitative characterization of the biological behavior of experimentally confirmed activators, and for qualitatively differentiating the activators from a large number of non-activators. From the predictor models it is suggested that the hydrophobic force and electrostatic interaction play an important role in hPXR-ligand binding, while steric factor contributes moderately to the binding.