Mechanisms of drug-target complex formation.

<p><b>(a)</b> Equilibria for rapid reversible inhibition via a one-step mechanism and slow-binding inhibition via a two-step induced-fit mechanism along with a schematic free-energy profile for this reaction. E denotes the enzyme, I the inhibitor, EI the initial enzyme-inhibitor complex, and EI* the final enzyme-inhibitor complex. In the case of InhA, the diphenyl ether inhibitors bind to the enzyme with bound oxidized cofactor NAD⁺, forming a ternary complex. The double-headed arrows in the energy profile highlight the importance of the barrier height for the kinetics of the reaction. <b>(b)</b> Schematic free-energy profiles for a slow-binding inhibitor (left) and a destabilized EI* state as a consequence of ligand removal or the presence of a rapid-reversible inhibitor (right). Each macrostate (EI, EI*) is obviously associated with many microstates.