Schnapp_2021_ChemMedChem_16_630

Reference

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.

PubMedSearch : Schnapp_2021_ChemMedChem_16_630
PubMedID: 33030297
Gene_locus related to this paper: human-FAP

Related information

Inhibitor Linagliptin
Gene_locus Linagliptin    human-FAP
Structure Linagliptin    human-FAP    6Y0F

Citations formats

Schnapp G, Hoevels Y, Bakker RA, Schreiner P, Klein T, Nar H (2021)
A Single Second Shell Amino Acid Determines Affinity and Kinetics of Linagliptin Binding to Type 4 Dipeptidyl Peptidase and Fibroblast Activation Protein
ChemMedChem 16 :630

Schnapp G, Hoevels Y, Bakker RA, Schreiner P, Klein T, Nar H (2021)
ChemMedChem 16 :630