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

A Single Second Shell Amino Acid Determines Affinity and Kinetics of Linagliptin Binding to Type 4 Dipeptidyl Peptidase and Fibroblast Activation Protein. ChemMedChem. 2020 Oct 08;: Authors: Schnapp G, Hoevels Y, Bakker R, Schreiner P, Thomas K, Nar H Abstract Type 4 dipeptidyl peptidase (DPP-4) and fibroblast activation protein alpha (FAP-α) are implicated in the pathophysiology of several metabolic disorders. Drugs targeting DPP-4 inhibition are beneficial for glycemic control, whereas FAP inhibition is a potential target for cancer therapies. In contrast to other gliptins, linagliptin displays unique FAP inhibition. We compared biophysical and structural mechanisms of linagliptin binding to DPP-4 and FAP. 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 shell amino acid difference: Asp663 (DPP-4) and Ala657 (FAP). The distinct pH dependence of enzymatic activities, differences in binding affinity and kinetics of linagliptin for DPP-4 and FAP are dependent on this single amino acid difference. PMID: 33030297 [PubMed - as supplied by publisher]
Source: ChemMedChem - Category: Chemistry Authors: Tags: ChemMedChem Source Type: research