New C-linked diarylheptanoid dimers as potential α-glucosidase inhibitors evidenced by biological, spectral and theoretical approaches

Xin-Yu Li; Tian Wang; Sheng-Li Wu; Xiao-Yan Huang; Yun-Bao Ma; Chang-An Geng

doi:10.1016/j.ijbiomac.2025.139496

New C-linked diarylheptanoid dimers as potential α-glucosidase inhibitors evidenced by biological, spectral and theoretical approaches

Int J Biol Macromol. 2025 Jan 6:139496. doi: 10.1016/j.ijbiomac.2025.139496. Online ahead of print.

Authors

Xin-Yu Li¹, Tian Wang², Sheng-Li Wu¹, Xiao-Yan Huang², Yun-Bao Ma², Chang-An Geng³

Affiliations

¹ Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China; University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China.
² Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China.
³ Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China; University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China. Electronic address: gengchangan@mail.kib.ac.cn.

PMID: 39778839
DOI: 10.1016/j.ijbiomac.2025.139496

Abstract

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by elevated blood glucose levels, generally due to defects of insulin action or secretion. Inhibition of α-glucosidase, an enzyme responsible for carbohydrate degradation, is a promising strategy for managing postprandial hyperglycemia in diabetic patients. In this study, two new C-linked diarylheptanoid dimers, kaemgalanganols A (1) and B (2), were isolated from K. galanga, which showed obvious inhibitory activity on α-glucosidase but weak activity on protein tyrosine phosphatase 1B (PTP1B). Kaemgalanganol B had an IC₅₀ value of 35.1 μM against α-glucosidase, obviously more potent than kaemgalanganol A (IC₅₀ = 78.5 μM) and acarbose (IC₅₀ = 363.0 μM). Enzyme kinetic study indicated that 2 was a reversible mixed-type inhibitor of α-glucosidase via non-competitive and anti-competitive inhibition modes. Fluorescence quenching and UV-visible spectroscopic study revealed that fluorescence quenching mechanism of 2 on α-glucosidase is a combination of dynamic quenching and static quenching, accompanied by non-radiative energy transfer. Compound 2 formed complex with α-glucosidase closer to the Tyr residue, and induced changes in both the microenvironment and peptide backbone. Surface hydrophobicity and CD spectra measurement indicated that 2 affected the function of α-glucosidase by decreasing the surface hydrophobicity of α-glucosidase as well as altering the secondary structure instead of the overall three-dimensional framework, which is consistent with the results of fluorescence experiment. Molecular docking manifested that compound 2 had a strong binding affinity (-7.27 kcal/mol) with α-glucosidase, higher than 1 (-9.82 kcal/mol) and acarbose (-4.48 kcal/mol), consistent with the enzyme inhibitory assay. Besides hydrogen bonds, electrostatic interactions and hydrophobic interactions played important roles in the binding of 2 with α-glucosidase. This study disclosed the inhibitory activity and mechanism of 2 against α-glucosidase, which provides a theoretical basis for the development of new antidiabetic drugs form K. galanga.

Keywords: Inhibition mechanism; Kaemgalanganols; Kaempferia galanga; Molecular docking; Spectral data; α-Glucosidase.