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

Abstract

Glucokinase (GK) activators (GKAs) are a long-sought therapeuticmodality for the treatment of type 2 diabetes. However, GKAs have failed in clinical trials, with the recent exception of dorzagliatin (HuaMedicine). A comprehensive approach using human islet perifusions, enzyme kinetics, X-ray crystallography, andmodeling 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 opento- 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 opento- 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.