title: Application of molecular modeling to urokinase inhibitors development.
abstract: Urokinase-type plasminogen activator (uPA) plays an important role in the regulation of diverse physiologic and pathologic processes. Experimental research has shown that elevated uPA expression is associated with cancer progression, metastasis, and shortened survival in patients, whereas suppression of proteolytic activity of uPA leads to evident decrease of metastasis. Therefore, uPA has been considered as a promising molecular target for development of anticancer drugs. The present study sets out to develop the new selective uPA inhibitors using computer-aided structural based drug design methods. Investigation involves the following stages: computer modeling of the protein active site, development and validation of computer molecular modeling methods: docking (SOL program), postprocessing (DISCORE program), direct generalized docking (FLM program), and the application of the quantum chemical calculations (MOPAC package), search of uPA inhibitors among molecules from databases of ready-made compounds to find new uPA inhibitors, and design of new chemical structures and their optimization and experimental examination. On the basis of known uPA inhibitors and modeling results, 18 new compounds have been designed, calculated using programs mentioned above, synthesized, and tested in vitro. Eight of them display inhibitory activity and two of them display activity about 10 μM.
authors: Research Computer Center, Moscow State University, Leninskie Gory 1, Building 4, Moscow 119992, Russia ; Dimonta Ltd., Nagornaya Street 15, Building 8, Moscow 117186, Russia.
authors: V B
authors: VB
authors: Sulimov
authors: Research Computer Center, Moscow State University, Leninskie Gory 1, Building 4, Moscow 119992, Russia ; Dimonta Ltd., Nagornaya Street 15, Building 8, Moscow 117186, Russia.
authors: E V
authors: EV
authors: Katkova
authors: Research Computer Center, Moscow State University, Leninskie Gory 1, Building 4, Moscow 119992, Russia ; Dimonta Ltd., Nagornaya Street 15, Building 8, Moscow 117186, Russia.
authors: I V
authors: IV
authors: Oferkin
authors: Research Computer Center, Moscow State University, Leninskie Gory 1, Building 4, Moscow 119992, Russia ; Dimonta Ltd., Nagornaya Street 15, Building 8, Moscow 117186, Russia.
authors: A V
authors: AV
authors: Sulimov
authors: Research Computer Center, Moscow State University, Leninskie Gory 1, Building 4, Moscow 119992, Russia.
authors: A N
authors: AN
authors: Romanov
authors: Research Computer Center, Moscow State University, Leninskie Gory 1, Building 4, Moscow 119992, Russia.
authors: A I
authors: AI
authors: Roschin
authors: Cardiology Research Center of Russian Ministry of Health 3rd Cherepkovskaia, No. 15a, Moscow 121552, Russia.
authors: I B
authors: IB
authors: Beloglazova
authors: Cardiology Research Center of Russian Ministry of Health 3rd Cherepkovskaia, No. 15a, Moscow 121552, Russia.
authors: O S
authors: OS
authors: Plekhanova
authors: Cardiology Research Center of Russian Ministry of Health 3rd Cherepkovskaia, No. 15a, Moscow 121552, Russia ; Faculty of Medicine, Lomonosov Moscow State University, Lomonosovskiy Prospect 31, Building 5, Moscow 119192, Russia.
authors: V A
authors: VA
authors: Tkachuk
authors: Lomonosov Moscow State University, Leninskie Gory 1, Moscow 119991, Russia.
authors: V A
authors: VA
authors: Sadovnichiy
mesh_terms: D001798:Blood Proteins / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D012984:Software; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D001798:Blood Proteins; C031220:urokinase inhibitor; D014568:Urokinase-Type Plasminogen Activator