A concise review on hPXR ligand-recognizing residues and structure-based strategies to alleviate hPXR transactivation risk

Abstract

The human pregnane X receptor (hPXR) regulates the expression of major drug metabolizing enzymes. A wide range of drug candidates bind and activate hPXR, and hence are at risk of increasing drug–drug interactions and reducing clinical efficacy. hPXR structural features that function as hot spots for ligand binding are identified and highlighted in this concise review. Based on literature structure–activity relationship data as case studies, structure-based strategies to mitigate hPXR transactivation are summarized for medicinal chemists.