Comparative docking assessment of glucokinase interactions with its allosteric activators

Area of Science:

• Biochemistry
• Pharmacology
• Computational Chemistry

Background:

• Glucokinase (GK) is crucial for glucose metabolism and insulin secretion, making it a therapeutic target for type 2 diabetes (T2D).
• Recent advancements in GK activators (GKAs), like RO-28-1675, highlight their potential in T2D management.
• GK activators feature a Y-shaped structure with three arms that interact with an allosteric site distinct from the glucose-binding site.

Purpose of the Study:

• To conduct a comparative docking assessment of Glucokinase activators (GKAs) at the allosteric site.
• To elucidate the binding interactions between GKAs and the enzyme's allosteric pockets.
• To provide insights for the rational design of novel and more effective GKAs for type 2 diabetes therapy.

Main Methods:

• Utilized Autodock4 for comparative molecular docking simulations.
• Analyzed the binding modes of GKAs within the identified aromatic/hydrophobic subpockets of the GK allosteric site.
• Correlated docking results with experimental data and simulated binding free energies.

Main Results:

• Docking revealed that the three arms of GKAs bind to distinct aromatic/hydrophobic subpockets at the allosteric site.
• Key residue Arg63 forms specific hydrogen bonds with allosteric activators in the first pocket.
• The second pocket exhibits diverse binding interactions, including aromatic, hydrophobic, and multiple hydrogen bonds, indicating potential for optimization.

Conclusions:

• The study's docking results are consistent with experimental findings, validating the computational approach.
• Understanding the specific binding interactions at the allosteric site provides a foundation for designing improved GKAs.
• The second binding pocket offers significant opportunities for further GKA optimization using aromatic heterocycles and hydrogen bond linkers.