Molecular Modeling as a New Approach to the Development of Urokinase Inhibitors

Proteolytic activity of urokinase plays an important role in negative remodeling of blood vessels, restenosis, tumor angiogenesis, and metastasizing, which necessitates the development of selective urokinase inhibitors. Using methods of computer modeling (docking, post processing, and direct docking) and quantum chemistry, we selected substances from the large compound database, analyzed their structures, and experimentally verified their inhibitor activity. New urokinase inhibitor candidates were proposed based on the theoretical predictions and experimental verification of compound activities. The process of modifying urokinase inhibitors based on (benzothiazol-3-yl)guanidine was developed. A new urokinase inhibitor (5-brom-benzothiazol-3-yl)guanidine, that can be effective for regulation of vascular remodeling and tumor angiogenesis, was created.