Molecular model of an interaction between factor Xa and DX-9065a, a novel factor Xa inhibitor: contribution of the acetimidoylpyrrolidine moiety of the inhibitor to potency and selectivity for serine proteases

Article abstract of DOI:10.1016/0223-5234(96)88248-1

Molecular modeling of a complex between factor Xa (FXa) and DX-9065a, a novel FXa inhibitor, has demonstrated a salt-bridge interaction of the amidinonaphthalene moiety of the inhibitor to the S1 site pocket of the enzyme and a crucial carboxyl group of the inhibitor for the FXa/thrombin selectivity. In the present study, we synthesized some DX-9065a derivatives and studied their interaction modes with FXa, trypsin and thrombin to evaluate the role of the acetimidoylpyrrolidine moiety. The docking study of the inhibitor in the FXa model provided a molecular model of the inhibitor-FXa complex showing a hydrophobic interaction of the pyrrolidine ring with an aryl binding site of FXa, and a hydrogen bond between the acetimidoyl group and the backbone carbonyl oxygen of Glu97. Comparison between the interaction mode of DX-9065a with FXa and those with trypsin and thrombin explained the inhibitory potencies of the enzymes.