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Abstract
Insulin-degrading enzyme (IDE) gene is one of the type 2 diabetes mellitus susceptibility genes specific to the Han Chinese population. IDE, a zinc-metalloendopeptidase, is a potential target for controlling insulin degradation. Potential lead compounds for IDE inhibition were identified from traditional Chinese medicine (TCM) through virtual screening and evaluation of their pharmacokinetic properties of absorption, distribution, metabolism, excretion, and toxicity. Molecular dynamics (MD) simulation was performed to validate the stability of complexes from docking simulation. The top three TCM compounds, dihydrocaffeic acid, isopraeroside IV, and scopolin, formed stable H–bond interactions with key residue Asn139, and were linked to active pocket residues His108, His112, and Glu189 through zinc. Torsion angle trajectories also indicated some stable interactions for each ligand with IDE. Molecular level analysis revealed that the TCM candidates might affect IDE through competitive binding to the active site and steric hindrance. Structural feature analysis reveals that high amounts of hydroxyl groups and carboxylic moieties contribute to anchor the ligand within the complex. Hence, we suggest the top three TCM compounds as potential inhibitor leads against IDE protein to control insulin degradation for type 2 diabetes mellitus.
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Acknowledgments
The research was supported by grants from the National Science Council of Taiwan (NSC101-2325-B-039-001), Asia University (100-asia-56), and China Medical University and Asia University (DMR-101-094, asia100-cmu-2). This study is also supported in part by Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH101-TD-B-111-004) and Taiwan Department of Health Cancer Research Center of Excellence (DOH101-TD-C-111-005). We are grateful to Asia University and the National Center of High-performance Computing for computer time and facilities.