Application of Molecular Modeling to Development of New Factor Xa Inhibitors.
In consequence of the key role of factor Xa in the clotting cascade and absence of its activity in the processes that do not affect coagulation, this protein is an attractive target for development of new blood coagulation inhibitors. Factor Xa is more effective and convenient target for creation of anticoagulants than thrombin, inhibition of which may cause some side effects. This study is aimed at finding new inhibitors of factor Xa by molecular computer modeling including docking SOL and postdocking optimization DISCORE programs. After validation of molecular modeling methods on well-known factor Xa inhibitors the virtual screening of NCI Diversity and Voronezh State University databases of ready-made low molecular weight species has been carried out. Seventeen compounds selected on the basis of modeling results have been tested experimentally in vitro. It has been found that 12 of them showed activity against factor Xa (IC50 = 1.8-40 μM). Based on analysis of the results, the new original compound was synthesized and experimentally verified. It shows activity against factor Xa with IC50 value of 0.7 μM.
Research Computer Center, Moscow State University, Leninskie Gory 1, Building 4, Moscow 119991, Russia ; Dimonta, Ltd., Nagornaya Street 15, Building 8, Moscow 117186, Russia.
Vladimir B
VB
Sulimov
Laboratory of Physical Biochemistry, National Research Center for Hematology, Russian Academy of Medical Sciences, Novyi Zykovskiy Proezd, 4a, Moscow 125167, Russia ; Laboratory of Biophysics and Physiology of Cell, Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Kosygin Street, 4, Moscow 119991, Russia.
Irina V
IV
Gribkova
Faculty of Chemistry, Moscow State University, Leninskie Gory 1, Building 3, Moscow 119991, Russia.
Maria P
MP
Kochugaeva
Research Computer Center, Moscow State University, Leninskie Gory 1, Building 4, Moscow 119991, Russia ; Dimonta, Ltd., Nagornaya Street 15, Building 8, Moscow 117186, Russia.
Ekaterina V
EV
Katkova
Research Computer Center, Moscow State University, Leninskie Gory 1, Building 4, Moscow 119991, Russia ; Dimonta, Ltd., Nagornaya Street 15, Building 8, Moscow 117186, Russia.
Alexey V
AV
Sulimov
Research Computer Center, Moscow State University, Leninskie Gory 1, Building 4, Moscow 119991, Russia.
Danil C
DC
Kutov
Faculty of Chemistry, Voronezh State University, Universitetskaya Plóshchaď 1, Voronezh 394006, Russia.
Khidmet S
KS
Shikhaliev
Faculty of Chemistry, Voronezh State University, Universitetskaya Plóshchaď 1, Voronezh 394006, Russia.
Svetlana M
SM
Medvedeva
Faculty of Chemistry, Voronezh State University, Universitetskaya Plóshchaď 1, Voronezh 394006, Russia.
Michael Yu
MY
Krysin
Laboratory of Biophysics and Physiology of Cell, Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Kosygin Street, 4, Moscow 119991, Russia ; Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Samory Mashela Street 1, Moscow 117198, Russia.
Elena I
EI
Sinauridze
Laboratory of Biophysics and Physiology of Cell, Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Kosygin Street, 4, Moscow 119991, Russia ; Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Samory Mashela Street 1, Moscow 117198, Russia ; Faculty of Physics, Moscow State University, Leninskie Gory 1, Building 2, Moscow 119991, Russia.
Fazoil I
FI
Ataullakhanov
D055808:Drug Discovery / Q000379:methods*; D065427:Factor Xa Inhibitors; D008958:Models, Molecular
D065427:Factor Xa Inhibitors