3VJM

Crystal structure of human depiptidyl peptidase IV (DPP-4) in complex with a prolylthiazolidine inhibitor #1

Summary for 3VJM

• Entry DOI: 10.2210/pdb3vjm/pdb
• Related: 3VJK 3VJL
• Descriptor: Dipeptidyl peptidase 4, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 1,3-thiazolidin-3-yl[(2S,4S)-4-{4-[2-(trifluoromethyl)quinolin-4-yl]piperazin-1-yl}pyrrolidin-2-yl]methanone, ... (5 entities in total)
• Functional Keywords: alpha/beta, beta-propeller, aminopeptidase, serine protease, signal-anchor, transmembrane, diabetes, glycoprotein, cell membrane, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 176361.59

Authors

Akahoshi, F.,Kishida, H.,Miyaguchi, I.,Yoshida, T.,Ishii, S. (deposition date: 2011-10-24, release date: 2012-08-15, Last modification date: 2024-10-09)

Primary citation

Yoshida, T.,Akahoshi, F.,Sakashita, H.,Sonda, S.,Takeuchi, M.,Tanaka, Y.,Nabeno, M.,Kishida, H.,Miyaguchi, I.,Hayashi, Y.
Fused bicyclic heteroarylpiperazine-substituted l-prolylthiazolidines as highly potent DPP-4 inhibitors lacking the electrophilic nitrile group
Bioorg.Med.Chem., 20:5033-5041, 2012

PubMed Abstract: Hypoglycemic agents with a mechanism of depeptidyl peptidase IV (DPP-4) inhibition are suitable for once daily oral dosing. It is difficult to strike a balance between inhibitory activity and duration of action in plasma for inhibitors bearing an electrophilic nitrile group. We explored fused bicyclic heteroarylpiperazine substituted at the γ-position of the proline structure in the investigation of L-prolylthiazolidines lacking the electrophilic nitrile. Among them, 2-trifluoroquinolyl compound 8g is the most potent, long-lasting DPP-4 inhibitor (IC(50) = 0.37 nmol/L) with high selectivity against other related peptidases. X-ray crystal structure determination of 8g indicates that CH-π interactions generated between the quinolyl ring and the guanidinyl group of Arg358 enhances the DPP-4 inhibitory activity and selectivity.

PubMed: 22824762
DOI: 10.1016/j.bmc.2012.06.033

Experimental method

X-RAY DIFFRACTION (2.1 Å)