Molecular Docking Studies of Natural Compounds Targeting Diabesity in Polycystic Ovary Syndrome via the AMPK Pathway

Polycystic Ovary Syndrome (PCOS) is a common endocrine and metabolic disorder characterized by insulin resistance, obesity, and hormonal imbalance, which collectively contribute to the development of diabesity. AMP-activated protein kinase (AMPK) plays a crucial role in regulating glucose and lipid metabolism and has emerged as a promising therapeutic target for the management of metabolic disturbances associated with PCOS. This study aimed to investigate the potential of selected natural compounds as modulators of AMPK-related protein targets using molecular docking approaches.A total of seventy-five natural compounds with reported antidiabetic, anti-obesity, and insulin-sensitizing activities were selected from literature and public databases. The compounds were prepared and optimized using Molecular Operating Environment (MOE) software and docked against two experimentally determined human AMPK structures, PDB IDs 4CFE and 5ISO. Physicochemical properties, drug-likeness, absorption, distribution, metabolism, excretion (ADME), and toxicity profiles of selected lead compounds were further evaluated using SwissADME and ProTox-II. The docking results with 4CFE and 5ISO revealed that the natural compounds Rutin, Curcumin and Silibinin demonstrated notable binding affinities, and they emerged as the top-performing compounds in the study. Physicochemical and ADME analyses indicated that Curcumin and Silibinin possessed favorable drug-likeness characteristics, acceptable bioavailability, and promising pharmacokinetic profiles. Toxicity prediction revealed acceptable safety profiles for the selected lead compounds, with no predicted carcinogenic or mutagenic effects. The findings suggest that Curcumin and Silibinin emerged as the most promising lead compounds for the management of diabesity associated with PCOS due to their favorable binding affinities, physicochemical properties, pharmacokinetic characteristics, and predicted safety profiles.

Keywords: Polycystic Ovary Syndrome, PCOS, Diabesity, AMPK, Molecular Docking, Curcumin, Silibinin, Rutin, Metformin.