Elsi Ferro
| Integrated Experimental and Computational Analysis of Benzimidazole α-Glucosidase Inhibitors for Pathway-Informed Design |
| Ferro Elsi 1, Laus Antonio 1, Atzeni Rossano 1 , Pieroni Enrico 1 , Valentini Maria 1 , Massimo Pisu 1 1 CRS4 (Center for Advanced Studies, Research and Development in Sardinia), Pula, Italy |
| Abstract Inhibition of α-glucosidase represents an established therapeutic strategy for the control of postprandial hyperglycemia in type 2 diabetes. Currently available inhibitors are often associated with adverse effects, therefore the identification of novel compounds with improved efficacy and safety profiles remains an important challenge. This work focuses on the combined experimental and computational investigation of benzimidazole derivatives as potential α-glucosidase inhibitors, with the aim of enabling pathway-informed optimization and rational design strategies. Selected compounds, synthesized through an efficient and environmentally friendly protocol, have shown promising inhibitory activity against α-glucosidase, with limited effects on α-amylase and no significant cytotoxicity in cellular models [1]. On the computational side, ongoing efforts are aimed at elucidating the molecular determinants of ligand binding and supporting the interpretation of experimental observations. In our approach, structure-based molecular modeling approaches are employed, including molecular docking to predict binding modes, classical molecular dynamics simulations to probe the stability of protein–ligand interactions, and cutting-edge enhanced sampling techniques [2] to explore conformational variability and particularly binding free/energy landscapes. Overall, this work aims to provide a framework for the rational characterization and prioritization of candidate α-glucosidase inhibitors, while contributing to pathway-informed optimization and design strategies. |
| References [1] Tocco G, Laus A, Manis C, Caboni P, Fais A, Era B. Sustainable Synthesis of 1,2-Disubstituted Benzimidazoles as Promising α-Glucosidase Inhibitors: In Vitro and In Silico Evaluation. Pharmaceuticals (Basel). 2025 Sep 30;18(10):1469. [2] Rizzi V, Aureli S, Ansari N, Gervasio FL. OneOPES, a Combined Enhanced Sampling Method to Rule Them All. J Chem Theory Comput. 2023 Sep 12;19(17):5731-5742 |