Insights into the binding of dorzagliatin with glucokinase: A molecular dynamics simulation

Human glucokinase (GK) is a potentially attractive target for diabetes, playing a prominent role in the control of glucose homeostasis. Dorzagliatin is the first GK activator (GKA) to enter phase III clinical trial. In this study, the possible binding mode of dorzagliatin with GK was investigated via the molecular simulation method. Two other systems in the absence of dorzagliatin and glucose were also studied to disclose the roles of dorzagliatin and glucose. The outcomes revealed that dorzagliatin can create the characteristic hydrogen bonds of GKA with Arg63, and Arg63 can form hydrogen bonds with nearby residues, making a tight binding hydrogen bond network around dorzagliatin. The presence of dorzagliatin can stabilize glucokinase for a period of time, and the binding of glucose may prevent the GK conformational change to a certain extent. Our results may be beneficial to mechanism understanding of GKA, and will be useful in design of novel GKAs for treating metabolic diseases.