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

Abstract

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 antico agulant drug. A three dimensional computational model for thrombin active site was construct ed and optimized for docking of small molecule organic compounds and calculating the ener gies of inhibitor-enzyme interactions. Novel racemic derivatives of 1 [2 (4 chlorophenyl thio)acetyl] 5 phenylpyrrolidine 2,4 dicarboxylic acids were synthesized for which Cl-π inter actions 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 proper ties show good correlations with the results of calculations.

Direct thrombin inhibitors: Patents 2002–2012 (Review)

“…It can bind to arginines, especially the positively-charged guanidine group interacting with the Asp-189 residue at the bottom of the S1 pocket. Hydrophobic amino acids, such as proline in the P2 position, can bind to the S2 pocket, and aromatic groups in the P3 position can interact with the lipophilic and aromatic fragments of the S3 pocket (25).…”

“…A recent study (25) demonstrated that the P1 fragment of the inhibitor does not need to contain a highly basic functional group to efficiently inhibit thrombin. The chlorophenyl fragment in the P1 position can be deeply inserted into the S1 pocket of the thrombin active site (25). In addition, heterocycle-substituted chlorophenyl incorporated into the P1 group was shown to provide more potent inhibitors (34).…”