The Bioorganic Mechanisms and Activity of Sulphonylurea Generations in Type II Diabetes Mellitus Treatment

Background/Objectives: Sulphonylureas (SUs) are a cost-effective first-line treatment for Type 2 Diabetes Mellitus (T2DM), yet the precise bioorganic mechanisms governing their activity and the variation in their hypoglycemic effects are not fully elucidated. This study aimed to computationally determine the structural basis for the activity of SUs on the sulphonylurea receptor 1 (SUR1) and to identify the factors responsible for their differing potencies and durations of action. Methods: A computational chemistry approach was employed to analyze first- and second-generation sulphonylureas. The methods included molecular docking to simulate drug-receptor binding, Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculations to estimate binding free energies, and the prediction of cytochrome P450 (CYP450) sites of metabolism to assess metabolic stability. Results: Molecular docking identified critical interactions between all SUs and the amino acid residues ARG 1300, ARG 1246, and ARG 4 on SUR1. The total hydrogen bond energy was found to be inversely proportional to the drugs’ potencies. Furthermore, the intrinsic reactivity of the predicted CYP450 metabolism sites was inversely proportional to the drugs’ observed half-lives. Conclusions: The activity of sulphonylureas on SUR1 is primarily driven by interactions with key arginine residues (ARG 1300, ARG 1246, and ARG 4). The variation in drug potency is explained by differences in total hydrogen bond energy, while the diversity in their hypoglycemic durations is attributed to their differing metabolic stability as determined by CYP450 intrinsic reactivity.