Molecular modeling studies of novel retro-binding tripeptide active-site inhibitors of thrombin

A novel series of retro-binding tripeptide thrombin active-site inhibitors was recently developed (Iwanowicz, E. I. et al. J. Med. Chem. 1994, 37, 2111 1). It was hypothesized that the binding mode for these inhibitors is similar to that of the first three N-terminal residues of hirudin. This binding hypothesis was subsequently verified when the crystal structure of a member of this series, BMS-183,507 ( N-[N-[N-[ 4-(Aminoiminomethyl)aminol-l-oxobutyl]- l-phenylalanyl]- l-allo-threonyl]- l-phenylalanine , methyl ester), was determined (Taberno, L. J. Mol. Biol. 1995, 246, 14 2) The methodology for developing the binding models of these inhibitors, the structure-activity relationships (SAR) and modeling studies that led to the elucidation of the proposed binding mode is described. The crystal structure of BMS-183,507/human α-thrombin is compared with the crystal structure of hirudin/human α-thrombin (Rydel, T. J. et al. Science 1990, 249, 227; 3 Rydel, T. J. et al. J. Mol Biol. 1991, 221, 583; 4 Grutter, M. G. et al. EMBO J. 1990, 9, 2361 5) and with the computational binding model of BMS-183,507. BMS-183,507 is a potent member of a series of retro-binding inhibitors of thrombin. We describe the modeling studies of these inhibitors and compare the crystal structure of BMS-183,507/thrombin with the crystal structure of hirudin/thrombin and with the computational binding model.