How residence time works in allosteric drugs

Drug residence time defines the duration the drug is bound to its protein target. It is a crucial determinant of drug action. Yet, a priori estimating it in the design could be the most challenging. The mechanisms of allosteric and orthosteric drugs differ in how they affect it. Binding at the active site, the residence time of orthosteric drugs is primarily affected by binding kinetics, which is not the case for allosteric drugs. Allosteric drugs determine the orthosteric drug residence time by the nature and extent of the population shift that they promote, which modulate the active site conformation. However, cooperative binding is bidirectional; orthosteric drug binding at the active site can increase (decrease) residence time at the allosteric site.