Microbial metabolite mimicry is a new concept that promises to deliver compounds that have minimal liabilities and enhanced therapeutic effects in a host. In a previous publication, we have shown that microbial metabolites of L-tryptophan, indoles, when chemically altered, yielded potent anti-inflammatory pregnane X Receptor (PXR)-targeting lead compounds, FKK5 and FKK6, targeting intestinal inflammation. Our aim in this study was to further define structure-activity relationships between indole analogs and PXR, we removed the phenyl-sulfonyl group or replaced the pyridyl residue with imidazolopyridyl of FKK6. Our results showed that while removal of the phenyl-sulfonyl group from FKK6 (now called CVK003) shifts agonist activity away from PXR towards the aryl hydrocarbon receptor (AhR), the imidazolopyridyl addition preserves PXR activity in vitro. However, when these compounds are administered to mice, that unlike the parent molecule, FKK6, they exhibit poor induction of PXR target genes in the intestines and the liver. These data suggest that modifications of FKK6 specifically in the pyridyl moiety can result in compounds with weak PXR activity in vivo. These observations are a significant step forward for understanding the structure-activity relationships (SAR) between indole mimics and receptors, PXR and AhR.

• Keywords
• Intestinal inflammation, Microbial mimics, Pregnane X receptor, Tryptophan catabolites,
• MeSH
• Adenocarcinoma MeSH
• Anti-Inflammatory Agents chemistry   pharmacology   MeSH
• Hepatocytes MeSH
• Indoles chemistry   pharmacology   MeSH
• Liver MeSH
• Protein Conformation MeSH
• Middle Aged MeSH
• Humans MeSH
• Molecular Mimicry MeSH
• Models, Molecular MeSH
• Molecular Structure MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Colonic Neoplasms MeSH
• Pregnane X Receptor chemistry   metabolism   MeSH
• Drug Design MeSH
• Intestines MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Names of Substances
• Anti-Inflammatory Agents MeSH
• Indoles MeSH
• Nr1i2 protein, mouse MeSH Browser
• Pregnane X Receptor MeSH

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,
• MeSH
• Pharmaceutical Preparations * MeSH
• Humans MeSH
• Drug Discovery MeSH
• Pregnane X Receptor * MeSH
• Receptors, Aryl Hydrocarbon * MeSH
• Receptors, Steroid * MeSH
• Intestines MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Pharmaceutical Preparations * MeSH
• Pregnane X Receptor * MeSH
• Receptors, Aryl Hydrocarbon * MeSH
• Receptors, Steroid * MeSH