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BioMed Research International
Volume 2015, Article ID 120802, 15 pages
http://dx.doi.org/10.1155/2015/120802
Research Article

Application of Molecular Modeling to Development of New Factor Xa Inhibitors

1Research Computer Center, Moscow State University, Leninskie Gory 1, Building 4, Moscow 119991, Russia
2Dimonta, Ltd., Nagornaya Street 15, Building 8, Moscow 117186, Russia
3Laboratory of Physical Biochemistry, National Research Center for Hematology, Russian Academy of Medical Sciences, Novyi Zykovskiy Proezd, 4a, Moscow 125167, Russia
4Laboratory of Biophysics and Physiology of Cell, Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Kosygin Street, 4, Moscow 119991, Russia
5Faculty of Chemistry, Moscow State University, Leninskie Gory 1, Building 3, Moscow 119991, Russia
6Faculty of Chemistry, Voronezh State University, Universitetskaya Plóshchaď 1, Voronezh 394006, Russia
7Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Samory Mashela Street 1, Moscow 117198, Russia
8Faculty of Physics, Moscow State University, Leninskie Gory 1, Building 2, Moscow 119991, Russia

Received 16 April 2015; Revised 12 August 2015; Accepted 20 August 2015

Academic Editor: Alfonso T. García-Sosa

Copyright © 2015 Vladimir B. Sulimov et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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.