Molecular Recognition of Ligands in Dipeptidyl Peptidase IV

Abstract

The serine protease dipeptidyl peptidase IV (DPP-IV) is a clinically validated target for the treatment of type II diabetes and has received considerable interest from the pharmaceutical industry over the last years. Concomitant with a large variety of published small molecule DPP-IV inhibitors almost twenty co-crystal structures have been released to the public as of May 2006. In this review, we discuss the structural characteristics of the DPP-IV binding site and use the available X-ray information together with published structure-activity relationship data to identify the molecular interactions that are most important for tight enzyme-inhibitor binding. Optimized interactions with the two key recognition motifs, i.e. the lipophilic S1 pocket and the negatively charged Glu 205/206 pair, result in large gains in binding free energy, which can be further improved by additional favorable contacts to side chains that flank the active site. First examples show that the lessons learned from the X-ray structures can be successfully incorporated into the design of novel DPP-IV inhibitors.

Serine peptidases: Classification, structure and function

“…Substrate selectivity for peptides shorter than 30 amino acids in length is derived from the two-domain architecture. An Nterminal seven-bladed propeller restricts access to the C-terminal a/b hydrolase domain, thus restricting size of substrate to approximately 30 amino acids in length [30,31]. On the basis of their selectivity toward smaller peptides and not full-length proteins, clan SC peptidases are thought to be particularly important in cell signaling mechanisms.…”

Discovery of DPP IV Inhibitors by Pharmacophore Modeling and QSAR Analysis followed by in silico Screening

“…[22] Various crystallographic studies on DPP IV have uncovered features involved in its ligand binding and enzymatic catalysis, most notably, the catalytic triad Ser630-Asp708-His740, the oxyanion hole Tyr 631-Tyr 547, the hydrophobic S1 pocket Tyr 631-Val 656-Trp 659-Tyr 662-Tyr 666-Val 711, the P2 region Arg 125-Asn 710, and the N-terminal recognition region Glu 205-Glu 206-Tyr 662. [23,24] Many research groups were, and still are, involved in the discovery and optimization of new DPP IV inhibitors as leads for new hypoA C H T U N G T R E N N U N G glycemic therapeutic agents for the treatment of type II diabetes. [25][26][27][28][29] These efforts culminated in the discovery and optimization of a number of reversible and irreversible DPP IV inhibitors, some of which are under clinical evaluation (for example, NVP-DPP728, Vildagliptin, P93/01).…”

Inhibition of dipeptidyl peptidase IV (DPP IV) is one of the mechanisms explaining the hypoglycemic effect of berberine

“…The molecular interactions of the highest ranking binding mode can be summarized in Figures 5 and 6. Clearly from the figures, the cationic nitrogen of berberine interacts with the negative charged carboxylate moiety of Glu-205, which is an important element of the anionic trap in DPP IV binding pocket [54]. On the other hand, the dimethoxylated aromatic ring in berberine is situated at around 4.2 Å from the guanidine moiety of Arg-125 suggesting a charge transfer attraction between the electron-rich aromatic ring and the positive charged guanidine group.…”