Aegeline from Aegle marmelos as a dual-target agonist for managing type II diabetes mellitus

Abstract

Type II Diabetes Mellitus (T2DM) is a multifactorial metabolic disorder requiring therapeutics that act on multiple pathways. A prominent therapeutic target is the Peroxisome Proliferator-Activated Receptor (PPAR) family, specifically the PPARg and PPARa subtypes. The mechanism of action of Aegeline, a natural compound extracted from Aegle marmelos leaves, is examined in a computational study and it is evaluated against synthetic PPAR agonists Pioglitazone, Rosiglitazone, and Fenofibrate. Full agonistic activity requires binding within the Ligand Binding Domain (LBD) and forming specific hydrogen bond interactions, which was found to be crucial through molecular docking analysis. The binding pose of Aegeline in the PPARg LBD was unique, as it did not have the conserved hydrogen bonds with His323 and Tyr473, which are characteristic of full agonists, suggesting that it acts as a partial agonist. In contrast, Aegeline showed a binding mode that was comparable to Fenofibrate, as it bonds with Tyr334 and Ala333. Based on these findings, Aegeline is believed to act as a PPARa agonist and a partial PPARg agonist, providing both antihyperglycemic and antilipidemic benefits.By using Aegeline, a natural compound that offers a promising lead, dual-target therapies that may have fewer side effects may be possible. In the future, the aim of research should be to verify these findings in vivo and explore their effect on diabetic complications.