Discovering novel α-aminoacyl-containing proline derivatives with potent and selective inhibitory activity against dipeptidyl peptidase IV: design, synthesis, biological evaluation, and molecular modeling.
On the basis of the enzyme-binding features of known potent inhibitors of dipeptidyl peptidase IV, novel α-aminoacyl-containing proline analogs (8Aa-8Ak, 8Ba-8Bj, 8Ca-8Ck, and 8Da-8Di) with the S configuration were designed, synthesized, and their activity profiled. Their structural features were determined by nuclear magnetic resonance (NMR) spectroscopy, low- and high-resolution mass spectroscopy. Five compounds (8Aa, 8Aj, 8Ch, 8Ck, and 8Dc) were shown to have promising inhibitory activities against dipeptidyl peptidase IV. Two of them, compounds 8Aa and 8Aj inhibited dipeptidyl peptidase IV with IC(50) values of 4.56 and 8.4 μm, respectively, and displayed no inhibition at other dipeptidyl peptidase IV. The possible binding modes of compounds 6, 7, 8Aa, and 8Aj with dipeptidyl peptidase IV were also explored by molecular docking simulation. This study provides promising new templates for the further development of antidiabetic agents.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
Xiaodong
X
Zhang
Jiang
J
Wang
Mingbo
M
Su
Zeng
Z
Li
Jingya
J
Li
Jia
J
Li
Hong
H
Liu
D001665:Binding Sites; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry* / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011392:Proline; D018819:Dipeptidyl Peptidase 4