Molecular Design of Potent Inhibitor Specific for Cathepsin B Based on the Tertiary Stucture 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-proline(CA-074)was show 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.