The reversed binding of beta-phenethylamine inhibitors of DPP-IV: X-ray structures and properties of novel fragment and elaborated inhibitors.
The co-crystal structure of beta-phenethylamine fragment inhibitor 5 bound to DPP-IV revealed that the phenyl ring occupied the proline pocket of the enzyme. This finding provided the basis for a general hypothesis of a reverse binding mode for beta-phenethylamine-based DPP-IV inhibitors. Novel inhibitor design concepts that obviate substrate-like structure-activity relationships (SAR) were thereby enabled, and novel, potent inhibitors were discovered.
Nordhoff
Sonja
S
Medicinal Chemistry, Santhera Pharmaceuticals, Im Neuenheimer Feld 518-519, D-69120 Heidelberg, Germany. sonja.nordhoff@santhera.com
Cerezo-Gálvez
Silvia
S
Feurer
Achim
A
Hill
Oliver
O
Matassa
Victor G
VG
Metz
Günther
G
Rummey
Christian
C
Thiemann
Meinolf
M
Edwards
Paul J
PJ
D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry* / Q000378:metabolism*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010627:Phenethylamines / Q000737:chemistry / Q000378:metabolism; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013552:Swine
D004791:Enzyme Inhibitors; D010627:Phenethylamines; C029261:phenethylamine; D011392:Proline; D018819:Dipeptidyl Peptidase 4