Functional and Mechanistic Explanation for the Unique Clinical Success of the Glucokinase Activator Dorzagliatin in the Treatment of Type 2 Diabetes.

UNLABELLED: Glucokinase (GK) activators (GKAs) are a long-sought therapeutic modality for the treatment of type 2 diabetes. However, GKAs have failed in clinical trials, with the recent exception of dorzagliatin (Hua Medicine). A comprehensive approach using human islet perifusions, enzyme kinetics, X-ray crystallography, and modeling studies was applied to compare the effects of dorzagliatin with those of the unsuccessful GKA MK-0941 (Merck Pharmaceuticals), which is well characterized both clinically and mechanistically. Dorzagliatin improved glucose-stimulated insulin secretion in a dose- and glucose-dependent manner, in contrast to MK-0941, which induced maximal insulin secretion at low doses and glucose concentrations. To understand these functional differences, the atomic resolution structure of the dorzagliatin-GK complex was determined and compared with the GK-MK-0941 structure. MK-0941 bound to a pocket accessible in both open and closed conformations; had a strong interaction with Y214, the mutation of which produces the most clinically severe activating mutation; and produced a high energy barrier for the open-to-closed transition. In contrast, dorzagliatin only bound favorably to the closed form of GK, interacting primarily with R63 and causing a low energy barrier for the open-to-closed transition. This provides the molecular rationale for the clinical success of dorzagliatin, which can guide the future development of next-generation allosteric activators of GK.

ARTICLE HIGHLIGHTS: The type 2 diabetes (T2D) treatment dorzagliatin has achieved singular success among its drug class, known as glucokinase (GK) activators (GKAs). A comprehensive approach using human islet perifusions, enzyme kinetics, X-ray crystallography, and modeling studies revealed the unique mechanism by which dorzagliatin activates GK. Dorzagliatin dose-dependently reduces the glucose threshold for stimulation of insulin secretion and binds preferably to the closed form of GK, preventing overstimulation of the enzyme. A renewed interest in GKAs, coupled with modern tools to assess their molecular interactions with GK, should guide the future development of novel GKA treatments for T2D.