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

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. This journal is © The Royal Society of Chemistry.