Structure Report for: 5LLS

Nar, H., Blaesse, M

Title: Comparative Analysis of Binding Kinetics and Thermodynamics of Dipeptidyl Peptidase-4 Inhibitors and Their Relationship to Structure
Schnapp G, Klein T, Hoevels Y, Bakker RA, Nar H
Ref: Journal of Medicinal Chemistry, 59:7466, 2016 : PubMed
Abstract


ESTHER: Schnapp_2016_J.Med.Chem_59_7466
PubMedSearch: Schnapp 2016 J.Med.Chem 59 7466
PubMedID: 27438064
Gene_locus related to this paper: pig-dpp4
Inhibitor(s) related to this paper: 6Z8

Abstract

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.