A Single Second Shell Amino Acid Determines Affinity and Kinetics of Linagliptin Binding to Type 4 Dipeptidyl Peptidase and Fibroblast Activation Protein.

ABSTRACT: Drugs targeting type 4 dipeptidyl peptidase (DPP-4) are beneficial for glycemic control, whereas fibroblast activation protein alpha (FAP-α) 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 6.6 pM; k_off 5.1×10^-5  s^-1 ), and weaker inhibitory potency to FAP (K_D 301 nM; k_off >1 s^-1 ). Co-structures of linagliptin with DPP-4 or FAP were similar except for one second

SUBMITTER: Schnapp G 

PROVIDER: S-EPMC7984154 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature