title: Molecular design of potent inhibitor specific for cathepsin B based on the tertiary structure prediction.
abstract: To design a potent inhibitor specific for cathepsin B (rat liver), the tertiary structure was predicted based on the crystal structure of the papain complexed with (+)-(2S,3S)-3-(1-[N-(3-methylbutyl)amino]leucylcarbonyl)oxirane-2- carbolylic acid (E-64-c), a thiol protease inhibitor. Taking advantage of the structural characteristics of the predicted active site, seventeen inhibitors were chemically synthesized by molecular modeling, and one of them, N-(L-3-trans-propylcarbamoyloxirane-2-carbonyl)-L-isoleucyl-L-p rol ine (CA-074) was shown to be the first potent inhibitor specific for cathepsin B. The relationship between the structure and inhibitory activity is discussed based on the model structure of the cathepsin B-inhibitor complex.
authors.affiliation: Research Center, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Sumiya
authors.forename: T
authors.initials: T
authors.lastname: Yoneda
authors.forename: K
authors.initials: K
authors.lastname: Kitamura
authors.forename: M
authors.initials: M
authors.lastname: Murata
authors.forename: C
authors.initials: C
authors.lastname: Yokoo
authors.forename: M
authors.initials: M
authors.lastname: Tamai
authors.forename: A
authors.initials: A
authors.lastname: Yamamoto
authors.forename: M
authors.initials: M
authors.lastname: Inoue
authors.forename: T
authors.initials: T
authors.lastname: Ishida
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002855:Chromatography, Thin Layer; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D007930:Leucine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010206:Papain / Q000737:chemistry; D051381:Rats; D014961:X-Ray Diffraction
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; C068250:N-(3-propylcarbamoyloxirane-2-carbonyl)-isoleucyl-proline; D002401:Cathepsin B; D010206:Papain; D007930:Leucine; C024974:E 64