5T4H

Human DPP4 in complex with ligand 34n

Summary for 5T4H

• Entry DOI: 10.2210/pdb5t4h/pdb
• Related: 5T4B 5T4E 5T4F
• Descriptor: Dipeptidyl peptidase 4, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: structure-based drug design, diabetes, dpp4 inhibitors, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 173934.13

Authors

Scapin, G. (deposition date: 2016-08-29, release date: 2016-10-05, Last modification date: 2024-10-16)

Primary citation

Pissarnitski, D.A.,Zhao, Z.,Cole, D.,Wu, W.L.,Domalski, M.,Clader, J.W.,Scapin, G.,Voigt, J.,Soriano, A.,Kelly, T.,Powles, M.A.,Yao, Z.,Burnett, D.A.
Scaffold-hopping from xanthines to tricyclic guanines: A case study of dipeptidyl peptidase 4 (DPP4) inhibitors.
Bioorg.Med.Chem., 24:5534-5545, 2016

PubMed Abstract: Molecular modeling of unbound tricyclic guanine scaffolds indicated that they can serve as effective bioisosteric replacements of xanthines. This notion was further confirmed by a combination of X-ray crystallography and SAR studies, indicating that tricyclic guanine DPP4 inhibitors mimic the binding mode of xanthine inhibitors, exemplified by linagliptin. Realization of the bioisosteric relationship between these scaffolds potentially will lead to a wider application of cyclic guanines as xanthine replacements in drug discovery programs for a variety of biological targets. Newly designed DPP4 inhibitors achieved sub-nanomolar potency range and demonstrated oral activity in vivo in mouse glucose tolerance test.

PubMed: 27670099
DOI: 10.1016/j.bmc.2016.09.007

Experimental method

X-RAY DIFFRACTION (2.61 Å)