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 advantag...

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Veröffentlicht in:Chemical & pharmaceutical bulletin 1992, Vol.40 (2), p.299-303
Hauptverfasser: SUMIYA, S, YONEDA, T, KITAMURA, K, MURATA, M, YOKOO, C, TAMAI, M, YAMAMOTO, A, INOUE, M, ISHIDA, T
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Sprache:eng
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Zusammenfassung: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.
ISSN:0009-2363
1347-5223
DOI:10.1248/cpb.40.299