Weak Microbial Metabolites: a Treasure Trove for Using Biomimicry to Discover and Optimize Drugs.
Journal
Molecular pharmacology
ISSN: 1521-0111
Titre abrégé: Mol Pharmacol
Pays: United States
ID NLM: 0035623
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
22
04
2020
accepted:
22
07
2020
pubmed:
9
8
2020
medline:
11
11
2020
entrez:
9
8
2020
Statut:
ppublish
Résumé
For decades, traditional drug discovery has used natural product and synthetic chemistry approaches to generate libraries of compounds, with 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. Furthermore, 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, with balance, we provide examples of where this emerging concept needs to be tested. SIGNIFICANCE STATEMENT: Microbial metabolite mimicry is a novel way to expand on the chemical repertoire of future drugs. The emerging concept is now explained using specific examples of the discovery of therapeutic leads from microbial metabolites.
Identifiants
pubmed: 32764096
pii: molpharm.120.000035
doi: 10.1124/molpharm.120.000035
pmc: PMC7485585
doi:
Substances chimiques
Biological Products
0
Indoles
0
Ligands
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
343-349Subventions
Organisme : NIDDK NIH HHS
ID : P01 DK094779
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA222469
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES030197
Pays : United States
Informations de copyright
Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.
Déclaration de conflit d'intérêts
We (S.M., Z.D.) have filed a patent application US 2019/0367475 A1: PXR agonists and uses thereof for gut barrier dysfunction and treatment prevention.
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