Chronic hyperglycemia is a metabolic disorder caused by insufficient insulin secretion, impaired insulin action, or a combination of both. Current oral hypoglycemic agents for managing Type 2 Diabetes (T2D) act through various mechanisms of action. Paederia scandens L. (commonly known as daun sembukan) is a perennial herb that grows in open fields, thickets and along riverbanks, with a long history of use in traditional medicine systems such as Chinese and Ayurvedic medicine for treating diverse ailments, including diabetes. In this study, we investigated the antidiabetic potential of compounds from P. scandens by evaluating their activity against four diabetes-related protein receptors: DPP-4, SGLT-2, PTP1B and FBPase. Among the tested ligands, three compounds — cosmetin, cynaroside and compound 39 — demonstrated superior pharmacological performance in both dynamic and kinetic evaluations. These ligands exhibited the highest binding affinities and more favorable pharmacokinetic profiles compared to other candidates, highlighting their potential as promising antidiabetic agents. © 2026, Walailak University. All rights reserved.