Exploring the inhibitory effect and mechanism of 3,4,5trihydroxybiphenyl on α-glucosidase: An integrated experimental and computational approach

Ruofan Guo¹Guohua Yu²Yuan Li¹Youyou Wang¹Huixia Fan¹Shuo Zhang²Chen Wang²Junhui Zhou¹Jian Yang¹Feng Gao³Zhiqiang Luo^1*

• ¹China Academy of Chinese Medical Sciences, Beijing, China
• ²Beijing University of Chinese Medicine, Beijing, Beijing Municipality, China
• ³Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China

3,4,5-Trihydroxybiphenyl (THB) is a naturally occurring compound derived from Sorbus pohuashanensis, primarily reported for its antifungal activity. However, its potential to inhibit αglucosidase remains unclear. In this study, we assessed the inhibitory effects of THB on α-glucosidase and explored the mechanism of inhibition through kinetic analysis, multispectral techniques, molecular docking and molecular dynamics simulations. Furthermore, a sucrose tolerance test was performed to evaluate the effects of THB on postprandial blood glucose (PBG) levels in mice. The results showed that THB exhibited a non-competitive and reversible inhibitory effect on α-glucosidase, with IC₅₀, Km, and Ki values of 11.52 μM, 0.69 ± 0.02 mM, and 26.26 ± 4.95 μM, respectively. THB showed a good affinity for α-glucosidase, with a KD value of 3.91 × 10 ⁻5 M. The interaction between THB and αglucosidase induced significant changes in the enzyme's microenvironment and secondary structure. The primary driving force for the binding of THB to α-glucosidase was hydrogen bonding. Additionally, THB could significantly reduce PBG levels in mice. Collectively, these findings suggest that THB holds potential as a natural inhibitor for the development of α-glucosidase-targeting agents.