Drug Repurposing of FDA Compounds against α-Glucosidase for the Treatment of Type 2 Diabetes: Insights from Molecular Docking and Molecular Dynamics Simulations

Abstract

Type 2 diabetes mellitus is a chronic health problem that can be controlled by slowing one’s carbohydrate metabolism by inhibiting α-glucosidase, an enzyme responsible for carbohydrate degradation. Currently, drugs for type 2 diabetes have limitations in terms of safety, efficiency, and potency, while cases are rapidly increasing. For this reason, the study planned and moved towards drug repurposing by utilizing food and drug administration (FDA)-approved drugs against α-glucosidase, and investigated the molecular mechanisms. The target protein was refined and optimized by introducing missing residues, and minimized to remove clashes to find the potential inhibitor against α-glucosidase. The most active compounds were selected after the docking study to generate a pharmacophore query for the virtual screening of FDA-approved drug molecules based on shape similarity. The analysis was performed using Autodock Vina (ADV)—based on binding affinities (−8.8 kcal/mol and −8.6 kcal/mol) and root-mean-square-deviation (RMSD) values (0.4 Å and 0.6 Å). Two of the most potent lead compounds were selected for a molecular dynamics (MD) simulation to determine the stability and specific interactions between receptor and ligand. The docking score, RMSD values, pharmacophore studies, and MD simulations revealed that two compounds, namely Trabectedin (ZINC000150338708) and Demeclocycline (ZINC000100036924), are potential inhibitors for α-glucosidase compared to standard inhibitors. These predictions showed that the FDA-approved molecules Trabectedin and Demeclocycline are potential suitable candidates for repurposing against type 2 diabetes. The in vitro studies showed that trabectedin was significantly effective with an IC50 of 1.263 ± 0.7 μM. Further investigation in the laboratory is needed to justify the safety of the drug to be used in vivo.

Synthesis, in vitro α‐Glucosidase Inhibition, DFT Calculations, and Molecular Docking Studies of Some New Substituted 2,5‐Bis(pyrazolyl)‐1,3,4‐oxadiazoles

“…The aromatic protons were found in the region of δ 7.0 ppm. Meanwhile, 13 C NMR signals also validate the recommended structures. The molecular ion peaks were detected in the EI-MS spectra of studied derivatives and the most characteristic fragment ion peak of m/z 247.0 was spotted in all mass spectra (Figure S3).…”

“…For FT-IR analysis, Agilent Technologies Cary 630 FTIR was used. The 1 H NMR and 13 C NMR spectra were recorded on Bruker DPX or AVANCE instruments at 500 MHz with chemical shifts in ppm. The CDCl 3 was used as solvent whereas TMS was the internal reference and J-values were determined in Hz.…”

“…However, some limitations, in terms of side effects and potency, are also associated with these drugs. [13] This intricacy encourages researchers to keep searching for more promising αglucosidase inhibitors with improved safety and efficiency. [14][15][16] Figure 1 is highlighting some recently reported potent αglucosidase inhibitors containing 1,3,4-oxadiazole (A-C) [17][18][19] and pyrazole (D-F) [20][21][22] molecular systems.…”

Trabectedin and Lurbinectedin Modulate the Interplay between Cells in the Tumour Microenvironment—Progresses in Their Use in Combined Cancer Therapy

“…It has been postulated as an α-glucosidase inhibitor with an in vitro IC 50 of 1.2 ± 0.7 µM, alongside demeclocycline. Nonetheless, this repositioning needs to be further assessed due to its systemic toxicity, hence, a well-justified safety study ought to be conducted [ 105 ].…”