title: Structural basis for the design of novel Schiff base metal chelate inhibitors of trypsin.
abstract: The crystal structures of the complexes of bovine trypsin with m-guanidinosalicylidene-l-alaninato(aqua)copper(II) hydrochloride (inhibitor 1), [N,N'-bis(m-guanidinosalicylidene)ethylenediaminato]copper(II) (inhibitor 2), and [N,N'-bis(m-amidinosalicylidene)ethylenediaminato]copper(II) (inhibitor 4) have been determined. The guanidine-containing trypsin-inhibitors (1 and 2) bind to the trypsin active site in a manner similar to that previously reported for amidine-containing inhibitors, for example, m-amidinosalicylidene-l-alaninato(aqua)copper(II) hydrochloride (inhibitor 3). However, the binding mode of the guanidino groups of inhibitors 1 and 2 to Asp189 in the S1 pocket of trypsin was found to be markedly different from that of the amidino group of inhibitor 3. The present X-ray analyses revealed that the interactions of the metal ion of the inhibitors with the active site residues of trypsin play a crucial role in the binding affinity to the trypsin molecule. These structural information and inhibitory activity data for amidine- and guanidine-containing Schiff base metal chelate inhibitors provide new avenues for designing novel inhibitors against physiologically important trypsin-like serine proteases.
authors.affiliation: Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Iyaguchi
authors.forename: Susumu
authors.initials: S
authors.lastname: Kawano
authors.forename: Kazuki
authors.initials: K
authors.lastname: Takada
authors.forename: Eiko
authors.initials: E
authors.lastname: Toyota
mesh_terms: D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D008958:Models, Molecular; D015394:Molecular Structure; D012545:Schiff Bases / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014357:Trypsin / Q000378:metabolism*; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002614:Chelating Agents; D012545:Schiff Bases; D014361:Trypsin Inhibitors; D003300:Copper; D014357:Trypsin