Bound Structures of Novel P3−P1‘ β-Strand Mimetic Inhibitors of Thrombin

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Abstract
The X-ray crystal structures of four β-strand-templated active site inhibitors of thrombin containing P1‘ groups have been determined and refined at about 2.1-Å resolution to crystallographic R-values between 0.148 and 0.164. Two of the inhibitors have an α-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 at 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 between 2.0 μM and 70 pM. The bound structures are used to intercorrelate the various binding constants and also lead to insightful inferences concerning binding at the S1‘ site of thrombin.