In Silico Analysis of Momordica charantia Triterpenoids as Adenosine Monophosphate-Activated Protein Kinase Ligands for Type 2 Diabetes Mellitus Therapy

Abstract

Type 2 diabetes mellitus continues to rise and calls for safe therapeutic leads. This study assessed the potential of triterpenoids from bitter melon (Momordica charantia) as AMP-activated protein kinase (AMPK) ligands at the ATP-binding site through an in silico approach. AMPK (PDB ID: 4QFG) was prepared in YASARA; nine M. charantia triterpenoids and metformin were docked in PLANTS. Redocking of staurosporine validated the protocol (RMSD 0.2376 Å; ≤2.0 Å). Kuguacin J (-89.9934), Karavilagenin B (-86.4084), and Kuguacin R (-85.8514) yielded lower (more favorable) docking scores than metformin (-56.5325) and interacted with hinge residues (Val96 and Glu94/Glu100). As expected, the co-crystallized ligand (staurosporine) showed the most favorable docking score and served as an internal benchmark for pocket definition. Kuguacin J and Kuguacin R fulfilled Lipinski's Rule of Five, whereas Karavilagenin B showed one logP violation. All three compounds demonstrated high predicted intestinal absorption, were predicted as AMES-negative, non-inhibitors of CYP2D6, and potential CYP3A4 substrates. These findings identify the three triterpenoids as promising AMPK ligand candidates warranting further experimental validation.