Comparative Analysis of Binding Kinetics and Thermodynamics of Dipeptidyl Peptidase‑4 Inhibitors and Their Relationship to Structure

The binding kinetics
and thermodynamics of dipeptidyl peptidase
(DPP)-4 inhibitors (gliptins) were investigated using surface plasmon
resonance and isothermal titration calorimetry. Binding of gliptins
to DPP-4 is a rapid electrostatically driven process. Off-rates were
generally slow partly because of reversible covalent bond formation
by some gliptins, and partly because of strong and extensive interactions.
Binding of all gliptins is enthalpy-dominated due to strong ionic
interactions and strong solvent-shielded hydrogen bonds. Using a congeneric
series of molecules which represented the intermediates in the lead
optimization program of linagliptin, the onset of slow binding kinetics
and development of the thermodynamic repertoire were analyzed in the
context of incremental changes of the chemical structures. All compounds
rapidly associated, and therefore the optimization of affinity and
residence time is highly correlated. The major contributor to the
increasing free energy of binding was a strong increase of binding
enthalpy, whereas entropic contributions remained low and constant
despite significant addition of lipophilicity.