The interaction mechanism of tepotinib and α-glucosidase: A prelude to control type 2 diabetes mellitus

Abstract

α-Glucosidase is associated with the enhancement in postprandial blood glucose. Therefore, inhibition of α-glucosidase activity could be considered as a potential strategy to control type 2 diabetes mellitus (DM). Tepotinib (TPT) as an enzyme inhibitor with a molecular formula of C29H28N6O2 has a distinct structure that may make it useful for interacting with α-glucosidase, causing conformational changes and inhibiting enzyme activity. In this study, the interaction mechanism of TPT and α-glucosidase was explored. The enzyme activity assay showed that TPT could inhibit α-glucosidase activity with the IC50 value of 0.071 ± 0.007 mg/mL (164 ± 16.5 µM), which was comparable with that of acarbose (IC50 = 0.045 ± 0.006 mg/mL = 255 ± 38.25 µM) as a clinical drug. It was further determined that Ser 241 and His 280 amino acid residues in the active site assist in the formation of the TPT-α-glucosidase complex mediated by hydrogen bonding and van der Waals forces, which might lead to the conformational folding of α-glucosidase to some extent. Additionally, the interaction of TPT and α-glucosidase reduced the surface hydrophobicity of the enzyme and altered the microenvironment around Tyr 158 amino acid residue in the active site. These findings suggested that TPT might be employed as a potential inhibitor of α-glucosidase activity, suggesting that it should be further explored in future studies to develop a TPT-based system for application in the amelioration of DM.