Rational Design and Evaluation of Novel TGR5 Agonists for Diabetes

Area of Science:

• Pharmacology
• Endocrinology
• Drug Discovery

Background:

• G protein-coupled receptor TGR5 agonists show metabolic benefits by stimulating GLP-1 secretion.
• Existing TGR5 agonists lack potency, exhibit side effects, and have not succeeded in clinical trials.
• Developing non-toxic, long-acting, and functionally selective TGR5 agonists remains a significant challenge.

Purpose of the Study:

• To establish a systematic, interdisciplinary pipeline for engineering optimal TGR5 agonists with antidiabetic properties.
• To identify lead compounds with beneficial characteristics for diabetes treatment.
• To elucidate the molecular mechanisms underlying TGR5 agonist activity in intestinal cells.

Main Methods:

• Utilized a combination of in silico, in vitro, and in vivo assays for drug candidate design and validation.
• Investigated molecular interactions within the TGR5 binding pocket.
• Analyzed TGR5 agonist-induced transcription in intestinal enteroendocrine cells.

Main Results:

• Identified two lead compounds demonstrating properties suitable for a successful TGR5 agonist.
• Uncovered molecular mechanisms of TGR5 agonist-induced TGR5 transcription in the gut.
• Characterized molecular interactions of lead candidates for enhanced stability and activity.

Conclusions:

• The developed pipeline offers a strategy for discovering targeted TGR5 therapeutics for metabolic diseases.
• The identified lead compounds and mechanistic insights advance the development of novel antidiabetic drugs.
• This approach has the potential to overcome limitations of current TGR5 agonist drug candidates.