Sítios de interação alternativos em receptores nucleares e sua viabilidade como alvos terapêuticos usando triagem computacional e experimental.

Abstract

Nuclear receptors can control transcription in eukaryotic cells in a ligand-dependent manner and, besides the ligand-binding pocket there is evidence of the existence of alternative ligand-binding sites on the surface, which can be addressed by small organic molecules that disrupt specific protein-protein interactions and thereby may antagonise NR function. Activation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) results in the induction of first-pass metabolism and drug efflux. Hereby PXR/CAR may cause adverse drug reactions or therapeutic failure of drugs. Therefore, PXR and/or CAR antagonists can minimise adverse effects or improve therapeutic efficiencies. Combination of cellular high-throughput screen identified CAR and PXR potent antagonists in a library of approved and investigational drugs. Further validated by cellular and in vitro assays, as well as molecular docking, suggesting additional or exclusive binding outside the classical ligand binding pocket. In conclusion, we here have identified three approved drugs as novel potent PXR antagonists and five potential CAR inverse agonists with differential receptor interaction profiles.