3VJK: Crystal Structure Of Human Depiptidyl Peptidase Iv (dpp-4) In Complex With Mp-513

Citation:
Abstract
Dipeptidyl peptidase IV (DPP-4) inhibition is suitable mechanism for once daily oral dosing regimen because of its low risk of hypoglycemia. We explored linked bicyclic heteroarylpiperazines substituted at the gamma-position of the proline structure in the course of the investigation of l-prolylthiazolidines. The efforts led to the discovery of a highly potent, selective, long-lasting and orally active DPP-4 inhibitor, 3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine (8 g), which has a unique structure characterized by five consecutive rings. An X-ray co-crystal structure of 8 g in DPP-4 demonstrated that the key interaction between the phenyl ring on the pyrazole and the S(2) extensive subsite of DPP-4 not only boosted potency, but also increased selectivity. Compound 8 g, at 0.03 mg/kg or higher doses, significantly inhibited the increase of plasma glucose levels after an oral glucose load in Zucker fatty rats. Compound 8 g (teneligliptin) has been approved for the treatment of type 2 diabetes in Japan.
PDB ID: 3VJKDownload
MMDB ID: 104210
PDB Deposition Date: 2011/10/24
Updated in MMDB: 2012/10
Experimental Method:
x-ray diffraction
Resolution: 2.49  Å
Source Organism:
Similar Structures:
Biological Unit for 3VJK: dimeric; determined by author and by software (PISA)
Molecular Components in 3VJK
Label Count Molecule
Proteins (2 molecules)
2
Dipeptidyl Peptidase 4(Gene symbol: DPP4)
Molecule annotation
Chemicals (19 molecules)
1
2
2
17
* Click molecule labels to explore molecular sequence information.

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