Drug Mimicry: Promiscuous Receptors PXR and AhR, and Microbial Metabolite Interactions in the Intestine

Abstract

Significant attrition limits drug discovery. The available chemical entities present with drug-like features contribute to this limitation. Using specific examples of promiscuous receptor-ligand interactions, a case is made for expanding the chemical space for drug-like molecules. These ligand-receptor interactions are poor candidates for the drug discovery process. However, provided herein are specific examples of ligand-receptor or transcription-factor interactions, namely, the pregnane X receptor (PXR) and the aryl hydrocarbon receptor (AhR), and itsinteractions with microbial metabolites. Discrete examples of microbial metabolite mimicry are shown to yield more potent and non-toxic therapeutic leads for pathophysiological conditions regulated by PXR and AhR. These examples underscore the opinion that microbial metabolite mimicry of promiscuous ligand-receptor interactions is warranted, and will likely expand the existing chemical space of drugs.

Keywords: biomimicry; chemical space; disease; drugs; metabolites; receptors.

Figure 1.. Tryptophan Intestinal Microbial Catabolites as Ligands and Agonists of Xenosensors, AhR and PXR.

A chart summarizes molecular effects of known human intestinal microbial metabolites of tryptophan at AhR and PXR receptors. Heat-map shows a semi-quantitative profile of interactions: (i) AFFINITY, is a measure of compound binding at the receptor ligand binding domain (dissociation constant ≈ K_D); (ii) POTENCY, refers to the concentration of the compound to produce 50% of maximal effect (half-maximal effective concentration ≈ EC₅₀); (iii) EFFICACY is the maximum response that can be reached by the compound.