Urokinase-type plasminogen activator (uPA) plays an important role in the regulation of diverse physiologic and pathologic\nprocesses. Experimental research has shown that elevated uPA expression is associated with cancer progression, metastasis, and\nshortened survival in patients, whereas suppression of proteolytic activity of uPA leads to evident decrease of metastasis. Therefore,\nuPA has been considered as a promisingmolecular target for development of anticancer drugs.Thepresent study sets out to develop\nthe new selective uPA inhibitors using computer-aided structural based drug design methods. Investigation involves the following\nstages: computer modeling of the protein active site, development and validation of computer molecular modeling methods:\ndocking (SOL program), postprocessing (DISCORE program), direct generalized docking (FLM program), and the application\nof the quantum chemical calculations (MOPAC package), search of uPA inhibitors among molecules from databases of readymade\ncompounds to find new uPA inhibitors, and design of new chemical structures and their optimization and experimental\nexamination. On the basis of known uPA inhibitors and modeling results, 18 new compounds have been designed, calculated using\nprograms mentioned above, synthesized, and tested in vitro. Eight of them display inhibitory activity and two of them display\nactivity about 10 ??M.
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