5LLS

Porcine dipeptidyl peptidase IV in complex with 8-(3-aminopiperidin-1-yl)-7-[(2-bromophenyl)methyl]-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione

5LLS の概要

• エントリーDOI: 10.2210/pdb5lls/pdb
• 分子名称: 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)
• 機能のキーワード: peptidase, inhibitor, complex, hydrolase
• 由来する生物種: Sus scrofa (Pig)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 364428.55

構造登録者

Nar, H.,Blaesse, M. (登録日: 2016-07-28, 公開日: 2016-09-14, 最終更新日: 2024-10-23)

主引用文献

Schnapp, G.,Klein, T.,Hoevels, Y.,Bakker, R.A.,Nar, H.
Comparative Analysis of Binding Kinetics and Thermodynamics of Dipeptidyl Peptidase-4 Inhibitors and Their Relationship to Structure.
J.Med.Chem., 59:7466-7477, 2016

PubMed Abstract: The binding kinetics and thermodynamics of dipeptidyl peptidase (DPP)-4 inhibitors (gliptins) were investigated using surface plasmon resonance and isothermal titration calorimetry. Binding of gliptins to DPP-4 is a rapid electrostatically driven process. Off-rates were generally slow partly because of reversible covalent bond formation by some gliptins, and partly because of strong and extensive interactions. Binding of all gliptins is enthalpy-dominated due to strong ionic interactions and strong solvent-shielded hydrogen bonds. Using a congeneric series of molecules which represented the intermediates in the lead optimization program of linagliptin, the onset of slow binding kinetics and development of the thermodynamic repertoire were analyzed in the context of incremental changes of the chemical structures. All compounds rapidly associated, and therefore the optimization of affinity and residence time is highly correlated. The major contributor to the increasing free energy of binding was a strong increase of binding enthalpy, whereas entropic contributions remained low and constant despite significant addition of lipophilicity.

PubMed: 27438064
DOI: 10.1021/acs.jmedchem.6b00475

実験手法

X-RAY DIFFRACTION (2.41 Å)