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.

Department of Molecular Pharmacology Albert Einstein College of Medicine Bronx NY 10461 USA; Department of Genetics Albert Einstein College of Medicine Bronx NY 10461 USA; Department of Medicine Albert Einstein College of Medicine Bronx NY 10461 USA

Departments of Cell Biology and Genetics Palacký University Olomouc 78371 Czech Republic

Sorbonne Université Inserm Centre de Recherche Saint Antoine CRSA AP HP Hôpital Saint Antoine Service de Gastroenterologie F 75012 Paris France; INRA UMR 1319 Micalis and AgroParisTech 78352 Jouy en Josas France; Paris Centre for Microbiome Medicine FHU Paris France

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