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Drug Repurposing for Diabetes Mellitus: In Silico and in Vitro Investigation of Drugbank Database for Α-Glucosidase Inhibitors Publisher Pubmed



Sadeghi M1 ; Miroliaei M1 ; Ghanadian M2
Authors
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Authors Affiliations
  1. 1. Faculty of Biological Science and Technology, Department of Cell and Molecular Biology & Microbiology, University of Isfahan, Isfahan, Iran
  2. 2. Department of Pharmacognosy, Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

Source: International Journal of Biological Macromolecules Published:2024


Abstract

The process of developing novel compounds/drugs is arduous, time-intensive, and financially burdensome, characterized by a notably low success rate and relatively high attrition rates. To alleviate these challenges, compound/drug repositioning strategies are employed to predict potential therapeutic effects for DrugBank-approved compounds across various diseases. In this study, we devised a computational and enzyme inhibitory mechanistic approach to identify promising compounds from the pool of DrugBank-approved substances targeting Diabetes Mellitus (DM). Molecular docking analyses were employed to validate the binding interaction patterns and conformations of the screened compounds within the active site of α-glucosidase. Notably, Asp352 and Glu277 participated in interactions within the α-glucosidase-ligand complexes, mediated by conventional hydrogen bonding and van der Waals forces, respectively. The stability of the docked complexes (α-glucosidase-compounds) was scrutinized through Molecular Dynamics (MD) simulations. Subsequent in vitro analyses assessed the therapeutic potential of the repositioned compounds against α-glucosidase. Kinetic studies revealed that “Forodesine” exhibited a lower IC50 (0.24 ± 0.04 mM) compared to the control, and its inhibitory pattern corresponds to that of competitive inhibitors. In-depth in silico secondary structure content analysis detailed the interactions between Forodesine and α-glucosidase, unveiling significant alterations in enzyme conformation upon binding, impacting its catalytic activity. Overall, our findings underscore the potential of Forodesine as a promising candidate for DM treatment through α-glucosidase inhibition. Further validation through in vitro and in vivo studies is imperative to confirm the therapeutic benefits of Forodesine in conformational diseases such as DM. © 2024 Elsevier B.V.
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