title: 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.
authors.affiliation: F. Hoffmann-La Roche Ltd, Discovery Research Basel, CH-4070 Basel, Switzerland. bernd.kuhn@roche.com
authors.forename: Bernd
authors.initials: B
authors.lastname: Kuhn
authors.forename: Michael
authors.initials: M
authors.lastname: Hennig
authors.forename: Patrizio
authors.initials: P
authors.lastname: Mattei
mesh_terms: D018360:Crystallography, X-Ray; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D015842:Serine Proteinase Inhibitors; D018819:Dipeptidyl Peptidase 4