Discovery of non-peptide GLP-1r natural agonists for enhancing coronary safety in type 2 diabetes patients.

Fatemeh Rajabian, Neda Shakour, Mehrdad Iranshahi, Farzin Hadizadeh, Saeideh Hoseinpoor, Sabikeh G Azimi, Hojjat Sadeghi-Aliabadi

Journal: Journal of biomolecular structure & dynamics 2025;43(7):3508-3525

PMID: 38165453

Abstract

This study explores the computational discovery of non-peptide agonists targeting the Glucagon-Like Peptide-1 Receptor (GLP-1R) to enhance the safety of major coronary outcomes in individuals affected by Type 2 Diabetes. The objective is to identify novel compounds that can activate the GLP-1R pathway without the limitations associated with peptide agonists. Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular disease (CVD) and mortality, which is attributed to the accumulation of fat in organs, including the heart. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are frequently used to manage T2DM and could potentially offer cardiovascular benefits. Therefore, this study examines non-peptide agonists of GLP-1R to improve coronary safety in type 2 diabetes patients. After rigorous assessments, two standout candidates were identified, with natural compound emerging as the most promising. This study represents a notable advancement in enhancing the management of coronary outcomes among individuals with type 2 diabetes. The computational methodology employed successfully pinpointed potential GLP-1R natural agonists, providing optimism for the development of safer and more effective therapeutic interventions. Although computational methodologies have provided crucial insights, realizing the full potential of these compounds requires extensive experimental investigations, crucial in advancing therapeutic strategies for this critical patient population.

Address: Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.; Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.; Department of Biochemistry and Biophysics, Faculty of Sciences, Mashhad Branch, Islamic Azad University, Mashhad, Iran.; International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran.; Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.; Department of Chemistry, Faculty of Sciences, University of Birjand, Birjand, Iran.; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.; Department of Pharmaceutical Chemistry, Isfahan University of Medical Sciences, Isfahan, Iran.; Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

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