Molecular design of potent inhibitor specific for cathepsin B based on the tertiary structure prediction.
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.
Sumiya
S
S
Research Center, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Yoneda
T
T
Kitamura
K
K
Murata
M
M
Yokoo
C
C
Tamai
M
M
Yamamoto
A
A
Inoue
M
M
Ishida
T
T
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
D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; C068250:N-(3-propylcarbamoyloxirane-2-carbonyl)-isoleucyl-proline; D002401:Cathepsin B; D010206:Papain; D007930:Leucine; C024974:E 64