Ligand trapping as a key mechanism governing drug residence time, binding affinity, and potency

Estimating binding affinity and potency is vital for the design of high-affinity compounds. Protein-ligand interactions are accompanied by conformational changes, resulting in complex kinetic behavior that influences drug activity and potency. From the general kinetic scheme of protein-ligand interactions, four limiting mechanisms emerge: lock-and-key, induced fit (IF), conformational selection (CS), and ligand trapping (LT). Together, these mechanisms define key structural and kinetic principles relevant to drug discovery. Here, I discuss the principles governing binding and dissociation, with particular emphasis on LT and its influence on dissociation kinetics. LT is the underlying mechanism that leads to slow dissociation and long residence times. As such, this mechanism is crucial for understanding the pharmacological activity of drugs that exhibit these properties and for guiding their rational design.