Inhibitory effect of phloroglucinol on α-glucosidase: Kinetics and molecular dynamics simulation integration study

• Published in: International journal of biological macromolecules Vol. 124; pp. 771 - 779
• Main Authors: Wan, Jia-Xin, Lim, Gyutae, Lee, Jinhyuk, Sun, Xiao-Bao, Gao, De-Ying, Si, Yue-Xiu, Shi, Xin-Lei, Qian, Guo-Ying, Wang, Qian, Park, Yong-Doo
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2019
• Subjects: Aggregation; Kinetics; Non-competitive inhibition; Phloroglucinol; α-Glucosidase; Aggregation; Non-competitive inhibition; Kinetics; α-Glucosidase; Phloroglucinol
• ISSN: 0141-8130; 1879-0003
• DOI: 10.1016/j.ijbiomac.2018.11.268

Regulation of α-glucosidase (EC 3.2.1.20) and its inhibitors is of great interest to researchers due to its clinical relevance as a target enzyme for the treatment of α-glucosidase-mediated diseases, such as type 2 diabetes mellitus and Pompe disease. In this study, we conducted a phloroglucinol-induced inhibition kinetics assay and performed computational molecular dynamics (MD) simulations to assess binding manner in α-glucosidase. The results showed that phloroglucinol reversibly inhibited α-glucosidase in a dose-dependent but non-competitive manner (Ki=2.07±0.16mM). Interestingly, the maximum peak wavelength and the hydrophobic surface remained unchanged during the inhibition reaction, with computational MD simulations further revealing that phloroglucinol bound in front of the active site pocket rather than in the α-glucosidase active site. Therefore, we speculate that phloroglucinol-specific inhibition is mild and the inhibitor likely binds to a single binding site near but not in the active site. Our study provided insight into the effects and mechanisms associated with a mild inhibitor of α-glucosidase activity and promotes fundamental research and potential applications of inhibitors for treatment of α-glucosidase-mediated clinical disease.