Inhibitor trapping

Inhibitor trapping, also known as ligand trapping or ligand entrapment, pertains to an inhibition mechanism in which a small molecule ligand becomes enclosed and locked within the structure of the protein target. During this process, the protein molecule acts as a trap, effectively immobilizing the small molecule within it. Simultaneously, the ligand confines the protein in a specific inhibited conformation by significantly reducing its dynamic movements. Inhibitor trapping leads to a substantial reduction in the dissociation rate of the ligand, resulting in increased binding affinity and activity.

Inhibitor trapping in hexokinase

The inhibitor trapping is contingent on the existence of open and closed protein conformations. The inhibitor gains entry in the open conformation and becomes entrapped during the formation of the closed form by preventing the transition to the open conformation. For example, the enzyme hexokinase that phosphorylates glucose in the first step of glycolysis can adopt open and closed conformation. The substrate glucose binds to the open form and induces the formation of a closed form where the phosphorylation reaction takes place. When the monosaccharide xylose is used instead of glucose, the hexokinase adopts the closed form, but it cannot reopen, leading to potent inhibition of the enzyme.

Ligand entrapment distinguishes itself from other models of inhibition, where the binding affinity is often evaluated by estimating the change in free binding energy caused by the transfer of the ligand from the solution to the protein's binding site. In contrast, the inhibitor trapping model suggests that the affinity of the inhibitor is influences by the protein's conformational dynamics, which determine whether the ligand will remain bound within its binding site