TY - JOUR T1 - <strong>WEAK MICROBIAL METABOLITES: A TREASURE TROVE FOR USING BIOMIMICRY TO DISCOVER AND OPTIMIZE DRUGS</strong> JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/molpharm.120.000035 SP - MOLPHARM-AR-2020-000035 AU - Zdenek Dvorak AU - Max Klapholz AU - Thomas P. Burris AU - Benjamin P Willing AU - Antimo Gioiello AU - Roberto Pellicciari AU - Francesco Galli AU - John March AU - Ryan B Sartor AU - Chang Kim AU - Maayan Levy AU - Sridhar Mani AU - Stephen J O'Keefe Y1 - 2020/01/01 UR - http://molpharm.aspetjournals.org/content/early/2020/08/06/molpharm.120.000035.abstract N2 - For decades, traditional drug discovery has utilized natural product and synthetic chemistry approaches to generate libraries of compounds, some ending as promising drug candidates. A complementary approach has been to adopt the concept of biomimicry of natural products and metabolites so as to improve multiple drug-like features of the parent molecule. In this effort, promiscuous and weak interactions between ligands and receptors are often ignored in a drug discovery process. In this emerging concepts' article, we highlight microbial metabolite mimicry, whereby parent metabolites have weak interactions with their receptors, that then have led to discrete examples of more potent and effective drug-like molecules. We show specific examples of parent metabolite mimics with potent effects in vitro and in vivo. Further we show examples of emerging microbial ligand-receptor interactions and provide a context in which these ligands could be improved as potential drugs. A balanced conceptual advance is provided in which we also acknowledge potential pitfalls - hyperstimulation of finely balanced receptor-ligand interactions could also be detrimental. However, on balance, we provide examples of where this emerging concept needs to be tested. Significance Statement The concept of microbial metabolite mimicry as a means to expand drug repertoires is new. Hitherto, there are very few proof-of-concept papers demonstrating utility of this concept. More recently, papers demonstrating mimicry of intestinal microbial metabolites could potentially expand the drug repertoire for diseases such as Inflammatory Bowel Disease. We opine that as more functional metabolite-receptor pairings are discovered, small molecular mimicry could be a significant effort in drug discovery. ER -