Diphenolic boldine, an aporphine alkaloid: inhibitory effect evaluation on α-glucosidase by molecular dynamics integrating enzyme kinetics

Abstract

Screening α-glucosidase inhibitors with novel structures is an important field in the development of anti-diabetic drugs due to their application in postprandial hyperglycemia control. Boldine is one of the potent natural antioxidants with a wide range of pharmacological activities. Virtual screening and biochemical inhibition kinetics combined with molecular dynamics simulations were conducted to verify the inactivation function of boldine on α-glucosidase. A series of inhibition kinetics and spectrometry detections were conducted to analyze the α-glucosidase inhibition. Computational simulations of molecular dynamics/docking analyses were conducted to detect boldine docking sites’ details and evaluate the key binding residues. Boldine displayed a typical reversible and mixed-type inhibition manner. Measurements of circular dichroism and fluorescence spectrum showed boldine changed the secondary structure and loosened the tertiary conformation of target α-glucosidase. The computational molecular dynamics showed that boldine could block the active pocket site through close interaction with binding key residues, and two phenolic hydroxyl groups of boldine play a core function in α-glucosidase inhibition via ligand binding. This investigation reveals the boldine function on interaction with the α-glucosidase active site, which provides a new inhibitor candidate.

Communicated by Ramaswamy H. Sarma

Keywords:

• Inhibition
• kinetics
• α-glucosidase
• boldine
• molecular dynamics

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Zhejiang Chinese Medical University Landmark Achievement Cultivation Project [grant number BZXCG-2022-26] and the Key Laboratory of Blood-stasis-toxin Syndrome of Zhejiang Province. Dr. Jinhyuk Lee was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2020R1I1A2071859) and the Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program (KGM5362111).