Mechanism of five flavonoids inhibiting NtMGAM based on molecular simulations

Abstract

AbstractRecent studies have showed that five flavonoids (Epigallocatechin gallate [EGCG], Rutin, Silibinin, Genistein, and Quercetin) are potential therapeutic agents for type II diabetes mellitus (T2DM). Our previous study revealed the mechanism of these five flavonoids with human islet amyloid peptide, but the mechanism of action with other T2DM‐related target proteins is unknown. In this study, we investigate the competitive inhibition mechanism of N‐terminal catalytic domain maltase glucose‐amylase (NtMGAM), which is another important target of T2DM, with the five types of flavonoids through molecular docking, molecular dynamics, and steered molecular dynamics. Our results show that the NtMGAM active pocket tends to bind to the aromatic nucleus. Moreover, EGCG and Rutin can potentially inhibit NtMGAM, and both molecules exhibit a larger binding capability with the active pocket than Acarbose. Compared with the hexasaccharide group, the pentasaccharide group has the advantage to bind with the NtMGAM active pocket, suggesting that the structure embedded into the active pocket should be inadvisable to oversize. Meanwhile, solvent molecules are a crucial factor affecting the binding stability of inhibitor with NtMGAM. In conclusion, this work is helpful to provide a theoretical basis for screening, modifying, and designing new therapeutic or preventive drugs targeting T2DM.