A semiempirical study on leupeptin: An inhibitor of cysteine proteases

In this work, we modeled leupeptin (Ac.Leu.Leu.Arg.CHO), a natural inhibitor of proteases, and the active site of papain, a cysteine protease, using as a template the crystal structure of a leupeptin-papain complex recently obtained by Schroder and co-workers [FEES Lett. 135(1), 38 (1993)] and including 11 amino acids relevant to the proteolytic activity of the enzyme. Our results show that the AM1 fully optimized leupeptin is more stable than is the leupeptin crystal structure by about 6.0 kcal/mol. Our results show also that in the modeled active center of papain the S-H ... N structure is favored. When the aldehyde is included in the calculation, however, proton transfer occurs with a strengthening of the S-... HIm(+)... O=C (Asn175) catalytic triad. The AM1 method reproduces fairly well the interactions between the enzyme and the host molecule. (C) 1997 John Wiley & Sons, Inc.