A SEMIEMPIRICAL STUDY ON LEUPEPTIN - AN INHIBITOR OF CYSTEINE PROTEASES

In this work, we modeled leupeptin (Ac.Leu.Leu.Arg.CHO), a natural inh ibitor of proteases, and the active site of papain, a cysteine proteas e, using as a template the crystal structure of a leupeptin-papain com plex recently obtained by Schroder and co-workers [FEES Lett. 135(1), 38 (1993)] and including 11 amino acids relevant to the proteolytic ac tivity of the enzyme. Our results show that the AM1 fully optimized le upeptin is more stable than is the leupeptin crystal structure by abou t 6.0 kcal/mol. Our results show also that in the modeled active cente r of papain the S-H ... N structure is favored. When the aldehyde is i ncluded in the calculation, however, proton transfer occurs with a str engthening of the S-... HIm(+)... O=C (Asn175) catalytic triad. The AM 1 method reproduces fairly well the interactions between the enzyme an d the host molecule. (C) 1997 John Wiley & Sons, Inc.