Drug design and optimisation at the pregnane X receptor

Abstract

Introduction: Drug-drug interactions are an increasing concern, particularly in the elderly due to polypharmacy, often resulting in reduced efficacy, adverse effects, and even hospitalisation. The Pregnane X Receptor (PXR) has emerged as a promising druggable target for mitigating these interactions, thanks to its promiscuity and ability to bind structurally diverse molecules. As a key regulator of drug-metabolising enzymes and transporters, PXR activation can significantly alter the pharmacokinetics of co-administered medications. Therefore, selective PXR antagonists could help minimise such interactions by preventing the overexpression of enzymes like CYP3A4, ultimately improving therapeutic efficacy and clinical outcomes.

Aims: The aim of this study was to use GSK002, a high affinity PXR antagonist as the lead molecule to design structures with the ability of analogous PXR modulation, through virtual screening and de novo techniques.