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      Application of Molecular Modeling to Development of New Factor Xa Inhibitors


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          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 (IC 50 = 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 IC 50 value of 0.7  μM.

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          Most cited references51

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          Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects

          Aims To evaluate apixaban single dose safety, tolerability, pharmacokinetics and pharmacodynamics and assess the effect of food on apixaban pharmacokinetics. Methods A double-blind, placebo-controlled, single ascending-dose, first-in-human study assessed apixaban safety, pharmacokinetics and pharmacodynamics in healthy subjects randomized to oral apixaban (n = 43; 0.5–2.5 mg as solution or 5–50 mg as tablets) or placebo (n = 14) under fasted conditions. An open label, randomized, two treatment crossover study investigated apixaban pharmacokinetics/pharmacodynamics in healthy subjects (n = 21) administered apixaban 10 mg in fasted and fed states. Both studies measured apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and prothrombin time (PT) or a modified PT (mPT). Results In the single ascending-dose study increases in apixaban exposure appeared dose-proportional. Median t max occurred 1.5–3.3 h following oral administration. Mean terminal half-life ranged between 3.6 and 6.8 h following administration of solution doses ≤2.5 mg and between 11.1 and 26.8 h for tablet doses ≥5 mg. Concentration-related changes in pharmacodynamic assessments were observed. After a 50 mg dose, peak aPTT, INR and mPT increased by 1.2-, 1.6- and 2.9-fold, respectively, from baseline. In the food effect study: 90% confidence intervals of geometric mean ratios of apixaban C max and AUC in a fed vs. fasted state were within the predefined no effect (80–125%) range. Apixaban half-life was approximately 11.5 h. The effect of apixaban on INR, PT and aPTT was comparable following fed and fasted administration. Conclusions Single doses of apixaban were well tolerated with a predictable pharmacokinetic/pharmacodynamic profile and a half-life of approximately 12 h. Apixaban can be administered with or without food.
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            pi-Stacking interactions. Alive and well in proteins.

            A representative set of high resolution x-ray crystal structures of nonhomologous proteins have been examined to determine the preferred positions and orientations of noncovalent interactions between the aromatic side chains of the amino acids phenylalanine, tyrosine, histidine, and tryptophan. To study the primary interactions between aromatic amino acids, care has been taken to examine only isolated pairs (dimers) of amino acids because trimers and higher order clusters of aromatic amino acids behave differently than their dimer counterparts. We find that pairs (dimers) of aromatic side chain amino acids preferentially align their respective aromatic rings in an off-centered parallel orientation. Further, we find that this parallel-displaced structure is 0.5-0.75 kcal/mol more stable than a T-shaped structure for phenylalanine interactions and 1 kcal/mol more stable than a T-shaped structure for the full set of aromatic side chain amino acids. This experimentally determined structure and energy difference is consistent with ab initio and molecular mechanics calculations of benzene dimer, however, the results are not in agreement with previously published analyses of aromatic amino acids in proteins. The preferred orientation is referred to as parallel displaced pi-stacking.
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              Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor xa inhibitors in development.

              For the past five decades, there has been little progress in the development of oral anticoagulants, with the choices being limited to the vitamin K antagonists (VKAs). The situation is changing with the development of orally active small molecules that directly target thrombin or activated factor X (FXa). The two agents in the most advanced stages of development are dabigatran etexilate and rivaroxaban, which inhibit thrombin and FXa, respectively. Both are approved in the EU and Canada for venous thromboprophylaxis in patients undergoing elective hip- or knee-replacement surgery. Other agents in the early stages of development include several FXa inhibitors (apixaban, DU 176b, LY 517717, YM 150, betrixaban, eribaxaban [PD 0348292] and TAK 442) and one thrombin inhibitor (AZD 0837). With a predictable anticoagulant response and low potential for drug-drug interactions, these new agents can be given in fixed doses without coagulation monitoring. This renders them more convenient than VKAs. While the anticoagulant effect of the new thrombin and FXa inhibitors is similar, differences in the pharmacokinetic and pharmacodynamic parameters may influence their use in clinical practice. Here, we compare the pharmacokinetic and pharmacodynamic features of these new oral agents.

                Author and article information

                Biomed Res Int
                Biomed Res Int
                BioMed Research International
                Hindawi Publishing Corporation
                21 September 2015
                : 2015
                : 120802
                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
                Author notes
                *Ekaterina V. Katkova: katkova@ 123456dimonta.com

                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.

                : 16 April 2015
                : 12 August 2015
                : 20 August 2015
                Research Article


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