Selective boron-containing thrombin inhibitors - X-ray analysis reveals surprising binding mode

Based on the structural comparison of the S1 pocket in different trypsin-li ke serine proteases, a series of Boc-D-trimethylsilylalanine-proline-boro-X pinanediol derivatives, with boro-X being different amino boronic acids, h ave been synthesized as inhibitors of thrombin. Among the novel compounds, a number of derivatives were synthesized which appeared to have sidechain v ariants too big to fit into the S1 pocket. Nevertheless, these compounds in hibited thrombin in the nM range. The X-ray structure of one of these inhib itors bound to the active side of thrombin reveals that a new binding mode is responsible for these surprising results. (C) 2000 Elsevier Science Ltd. All rights reserved.