Fig. 1
From: Protein conformational flexibility modulates kinetics and thermodynamics of drug binding
Models of drug–target binding. a Schematic diagram of a one-barrier drug–target binding free energy profile. A one-step model with one free energy barrier is used to derive the experimental rate constants. The figure and equations show how the steady-state rate constants relate to the free energy differences shown. The residence time of a drug bound to its target, τ (which is the reciprocal of the rate constant for dissociation of the drug–target complex, k off), results from the “difference” in free energy between the transition state (TS) and the bound ground state (GS), ΔG off. The red arrows indicate that prolongation of the τ can be achieved by stabilizing the GS (increasing the magnitude of ΔG D), destabilizing the TS (increasing ΔG on) or a combination of both (i.e., \(K_{{\rm {off}}} \propto {e}^{\frac{{ - \Delta G_{{\rm {off}}}}}{{kT}}} = K_{\rm {D}}{e}^{\frac{{ - \Delta G_{{\rm {on}}}}}{{kT}}}\)). b Diagram schematically illustrating different mechanisms of drug binding involving protein conformational changes. R and RC denote two different conformations of the protein, the latter requires conformational changes for ligand binding. These may occur by conformational selection (blue path) or by induced fit upon formation of an encounter complex [RL]# (red path), or by a combination of the two mechanisms. Binding proceeds through an energetically unfavorable intermediate state (TS in panel A or a local minimum in a 2 (or more)-step binding free energy profile) that, in the conformational selection and induced fit mechanisms, corresponds, respectively, to the R+L or [RL]# state of the system); the final complex is denoted by [RL]. k C/–C and k 2/−2 are the rates of intrinsic and ligand-induced protein conformational transitions, respectively; k 1/−1 and k C1/−C1 are rates of formation of the bound and encounter complexes, assuming that the protein is in conformations R and RC, respectively; k off and k on are experimentally observed off- and on–binding rates. The gray path and third equation describe the pseudo-one-step binding process shown in (a) is used to derive the experimental rate constants
