Design of small-molecule thrombin inhibitors based on the cis-5-phenylproline scaffold

The design of novel organic compounds containing no strongly basic amidine or guanidine functional groups typical of serine protease inhibitors was performed to develop an oral anticoagulant drug. A three-dimensional computational model for thrombin active site was constructed and optimized for docking of small-molecule organic compounds and calculating the energies of inhibitor-enzyme interactions. Novel racemic derivatives of 1-[2-(4-chlorophenylthio)acetyl]-5-phenylpyrrolidine-2,4-dicarboxylic acids were synthesized for which Cl-π interactions between the inhibitors and the S1 pocket of thrombin active site are predicted by modeling. The compounds synthesized deactivate thrombin in vitro and the inhibition properties show good correlations with the results of calculations.