Discovery of new binding elements in DPP-4 inhibition and their applications in novel DPP-4 inhibitor design.
Probing with tool molecules, and by modeling and X-ray crystallography the binding modes of two structurally distinct series of DPP-4 inhibitors led to the discovery of a rare aromatic fluorine H-bond and the spatial requirement for better biaryl binding in the DPP-4 enzyme active site. These newly found binding elements were successfully incorporated into novel DPP-4 inhibitors.
Liang
Gui-Bai
GB
gui-bai_liang@merck.comMerck Research Laboratories, Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
Qian
Xiaoxia
X
Biftu
Tesfaye
T
Singh
Suresh
S
Gao
Ying-Duo
YD
Scapin
Giovanna
G
Patel
Sangita
S
Leiting
Barbara
B
Patel
Reshma
R
Wu
Joseph
J
Zhang
Xiaoping
X
Thornberry
Nancy A
NA
Weber
Ann E
AE
D001665:Binding Sites; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry*; D054873:Dipeptidyl-Peptidase IV Inhibitors; D015195:Drug Design; D005461:Fluorine / Q000737:chemistry; D005998:Glycine / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008962:Models, Theoretical; D008968:Molecular Conformation; D012984:Software; D015091:beta-Alanine / Q000737:chemistry
D054873:Dipeptidyl-Peptidase IV Inhibitors; D015091:beta-Alanine; D005461:Fluorine; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D005998:Glycine