article · Arabian Journal of Chemistry
Mohamed OuabaneThis research investigated thirty-one 4-amino-1,2,4-triazole derivatives with known activity against the enzyme alpha-glucosidase to support the development of treatments for diabetes mellitus. Using three-dimensional quantitative structure-activity relationship modeling, researchers built predictive computational models to identify structural features that enhance biological activity. Based on these insights, four new inhibitor molecules were designed and evaluated computationally for their pharmacological and safety profiles. Molecular docking and 100-nanosecond molecular dynamics simulations showed that one proposed compound, designated M1, maintained stable interactions with the target receptor. Additionally, quantum chemical analyses identified the key reactive centres of the molecule. The computational findings highlight compound M1 as a stable and potentially active candidate that warrants physical synthesis and experimental biological testing.
Diabetes mellitus is a widespread chronic condition that requires effective management of blood sugar levels. Inhibiting the enzyme alpha-glucosidase is an established therapeutic strategy to control glucose absorption. By using advanced computer modeling to design and screen improved chemical candidates before laboratory synthesis, researchers can significantly accelerate the early-stage discovery of safer and more potent antidiabetic medicines.
This work is at an early computational discovery stage, far from clinical use or near-term commercialisation. It primarily enables pharmaceutical researchers and drug discovery teams to select promising candidates for physical synthesis and wet-lab validation. Moving compound M1 toward commercial relevance will require laboratory synthesis, in vitro enzymatic assays, cell-based evaluations, and extensive pre-clinical testing to confirm its efficacy and safety profile.
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Diabetes mellitus is a chronic and non-infectious metabolic disorder caused by insufficient insulin secretion. This study investigated a set of thirty-one 4-amino-1,2,4-triazole derivatives, experimentally evaluated for their α-glucosidase activity against diabetes mellitus, using the three-dimensional quantitative structure–activity relationship (3D-QSAR) approach. The recommended CoMFA and CoMSIA/EHA models showed good predictive ability, manifested by high R2 values and important Q2 values. The molecular structural features offered by the CoMFA and CoMSIA/EHA contour maps had a significant impact on the determination of appropriate groups to enhance activity. Hence, four new 4-amino-1,2,4-triazole inhibitors were proposed and designed with good predicted α-glucosidase activity. The pharmacological and ADME-Tox properties of the four recommended molecules were predicted and examined. Molecular docking studied the interaction modes between the targeted receptor and 4-amino-1,2,4-triazole derivatives; it showed good stability for the new title molecule M1. Furthermore, molecular dynamics simulation at 100 ns and MM/PBSA approach results demonstrated an acceptable stability and the interactive force of the compound M1. Finally, the most nucleophilic and electrophilic centers of the compounds C25 and M1 were determined using quantum analysis. The current work encourages further experimental and scientific research on M1 molecule as a potent α-glucosidase inhibitor.
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DOI: 10.1016/j.arabjc.2024.105656
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