Hoevels Y

References (2)

Title : A Single Second Shell Amino Acid Determines Affinity and Kinetics of Linagliptin Binding to Type 4 Dipeptidyl Peptidase and Fibroblast Activation Protein - Schnapp_2021_ChemMedChem_16_630
Author(s) : Schnapp G , Hoevels Y , Bakker RA , Schreiner P , Klein T , Nar H
Ref : ChemMedChem , 16 :630 , 2021
Abstract : Drugs targeting type 4 dipeptidyl peptidase (DPP-4) are beneficial for glycemic control, whereas fibroblast activation protein alpha (FAP-alpha) is a potential target for cancer therapies. Unlike other gliptins, linagliptin displays FAP inhibition. We compared biophysical and structural characteristics of linagliptin binding to DPP-4 and FAP to better understand what differentiates linagliptin from other gliptins. Linagliptin exhibited high binding affinity (K(D) ) and a slow off-rate (k(off) ) when dissociating from DPP-4 (K(D) 6.6pM; k(off) 5.1x10(-5) s(-1) ), and weaker inhibitory potency to FAP (K(D) 301nM; k(off) >1s(-1) ). Co-structures of linagliptin with DPP-4 or FAP were similar except for one second shell amino acid difference: Asp663 (DPP-4) and Ala657 (FAP). pH dependence of enzymatic activities and binding of linagliptin for DPP-4 and FAP are dependent on this single amino acid difference. While linagliptin may not display any anticancer activity at therapeutic doses, our findings may guide future studies for the development of optimized inhibitors.
ESTHER : Schnapp_2021_ChemMedChem_16_630
PubMedSearch : Schnapp_2021_ChemMedChem_16_630
PubMedID: 33030297
Gene_locus related to this paper: human-FAP

Title : Comparative Analysis of Binding Kinetics and Thermodynamics of Dipeptidyl Peptidase-4 Inhibitors and Their Relationship to Structure - Schnapp_2016_J.Med.Chem_59_7466
Author(s) : Schnapp G , Klein T , Hoevels Y , Bakker RA , Nar H
Ref : Journal of Medicinal Chemistry , 59 :7466 , 2016
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.
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