Generation of ligand conformations in continuum solvent consistent with protein active site topology: application to thrombin.

Using the crystal structure of an inhibitor complexed with the serine protease thrombin (PDB code ) and the functional group definitions contained within the Catalyst software, a representation of the enzyme's active site was produced (structure-based pharmacophore model). A training set of 16 homologous non-peptide inhibitors whose conformations had been generated in continuum solvent (MacroModel) and clustered into conformational families (XCluster) was regressed against this pharmacophore so as to obtain a 3D-QSAR model. To test the robustness of the resulting QSAR model, the synthesis of a series of non-peptide thrombin inhibitors based on arylsuphonyl derivatives of an aminophenol ring linked to a pyridyl-based S1 binding group was undertaken. These compounds served as a test set (20-24). The crystal structure for the novel symmetrical disulfonyl compound 24, in complex with thrombin, has been solved. Its calculated binding mode is in general agreement with the crystallographically observed one, and the predicted K(i) value is in close accord with the experimental value.