Bound structures of novel P3-P1 ' beta-strand mimetic inhibitors of thrombin

The X-ray crystal structures of four P-strand-templated active site inhibit ors of thrombin containing P1' groups have been determined and refined at a bout 2.1-Angstrom resolution to crystallographic R-values between 0.148 and 0.164. Two of the inhibitors have an alpha-ketoamide functionality at the scissile bond; the other two have a nonhydrolyzable electrophilic group at the P1' position. The binding of lysine is compared with that of arginine a t the S1 specificity site, while that of D,L-phenylalanine enantiomorphs is compared in the S3 region of thrombin. Four different P1' moieties bind at the S1' subsite in three different ways. The binding constants vary betwee n 2.0 mu M and 70 pM, The bound structures are used to intercorrelate the v arious binding constants and also lead to insightful inferences concerning binding at the S1' site of thrombin.