Phytochemicals of Momordica charantia L. as Potential GSK-3 Inhibitors: A Comprehensive In-Silico Study on Antidiabetic Activity and Pharmacokinetic Properties

AbstractDiabetes mellitus (DM) is a chronic, non-infectious metabolic disorder that disrupts thenormal regulation of carbohydrate, lipid, and protein metabolism. This condition ischaracterized by sustained hyperglycemia due to insulin dysregulation. DM is primarilyclassified into two types: type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus(T2DM). T1DM is an autoimmune disorder wherein the immune system attacks anddestroys insulin-producing β-cells in the pancreas. T2DM, the most prevalent form, arisesdue to a combination of insulin resistance, inadequate insulin secretion and lifestyledisorders. Globally, T2DM accounts for nearly 90–95% of all diabetes cases, posing amajor burden on public health systems. The present study aimed to investigate theinhibitory potential of plant-derived metabolites against Glycogen Synthase Kinase-3(GSK-3), a key regulatory enzyme implicated in the pathogenesis of type 2 diabetes mellitus(T2DM). GSK-3 plays a critical role in glucose metabolism by phosphorylating andinactivating glycogen synthase (GS), the enzyme responsible for converting glucose intoglycogen. In its active state, GSK-3 prevents glycogen synthesis, leading to elevated bloodglucose levels. Targeting GSK-3 represents a promising therapeutic strategy for T2DMmanagement. Hence, the identification of novel GSK-3 inhibitors from plant-basedbioactive compounds holds significant potential for the development of safer and moreeffective antidiabetic agents. In recent years, computer-aided drug discovery and design(CADD) tools have played a pivotal role in accelerating new drug discovery process. Thecurrent study employed an in-silico docking approach to explore the antidiabetic potentialof bioactive compounds derived from Momordica charantiaL.(bitter melon), a medicinalplant well known for its diverse pharmacological properties, including hypoglycemic,anticancer, antiviral, anti-inflammatory, and cholesterol-lowering effects. Among the tenphytoconstituents evaluated against the diabetes-related target protein GSK-3, fivecompounds demonstrated superior binding affinities compared to the reference GSK-3inhibitor drug Tideglusib (binding affinity: –8.2 kcal/mol). These compounds werecucurbitin (–9.4 kcal/mol), cucurbitacins (–8.7 kcal/mol), momordicinin (–8.6 kcal/mol),momordenol (–8.3 kcal/mol), and cycloartenol (–8.3 kcal/mol). Further simulative analysisrevealed that these lead compounds exhibit favorable pharmacokinetic and toxicityHigh Technology Letters profiles, indicating good oral bioavailability and minimal predicted toxicity. These findingssuggest that bioactive metabolites of Momordica charantiaL.may serve as potent GSK-3inhibitors with therapeutic potential in the management of type 2 diabetes mellitus.