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  • br Materials and methods br Results br Conclusions In


    Materials and methods
    Conclusions In general, the drug design process is very laborious, expensive and prone to errors. Various computational methods including docking and algorithms based on molecular dynamics and/or quantum chemistry can help considerably at the early stage of structure-based drug design. In this work, we managed to obtain FXa inhibitors by using molecular modelling that underlines its efficacy in the drug development. Three separate iterations of in silico screening were performed and resulted in the fact that 12 of 40 compounds tested in vitro turned to be moderate inhibitors of FXa with micromolar activity. Moreover, one compound, VGY-0224989, was determined to possess selectivity over trypsin, thrombin, factor IXa, and factor XIa. Although this study did not imply conducting robust validation of the semiempirical method as postprocessing, its usefulness was demonstrated, especially, in revealing false positives emerged when selection of candidates is only docking-based. Obviously, simplified calculation of ΔH, relatively slight accounting for ΔS, and a rigid model of protein could influence on the overall accuracy of postprocessing, and the further modifications of this methodology, probably, will increase its prediction power.
    Acknowledgements The work was financially supported by the Russian Science Foundation, Agreement no. 15-11-00025-П in the part that includes molecular modelling, virtual screening, and design of inhibitors. The experimental testing was supported by grant from the Russian Fund for Basic Research (17-00-00481) and the Presidium of the Russian Academy of Sciences (Fundamental principles of physiological adaptations technology’). The research is carried out using the equipment of the shared research facilities of HPC computing resources at Lomonosov Moscow State University.
    Case Description
    Discussion Thrombosis of the deep cerebral veins develops very rarely, and approximately 6% of patients with cerebral venous thrombosis develop deep cerebral venous thrombosis. DCVT often leads to death or major long-term sequelae. It is an uncommon disease, arising from various causes, including infection, 15 australia disease, anemia, inflammatory diseases, and trauma. Women are affected 3 times more often than men. Clinical manifestations of DCVT, including headache, nausea, vomiting, focal neurologic deficits, hemiparesis, aphasia, seizures, coma, and death, are complex and nonspecific. In CT scans, direct and indirect signs of CVT, including the cord sign in the superior sagittal sinus or cortical vein and the empty delta sign in CT scans with contrast, are well documented. They are often not primarily identified. CT angiogram, MRI, and MRV are valid techniques in CVT diagnosis and follow-up. Thrombosis appears as an absence of flow void on spin-echo images and lack of signal in angiographic techniques. We found bilateral hyperintensities in diffusion-weighted imaging and fluid-attenuated inversion recovery sequences in the thalamus and basal ganglia. Edema observed on imaging in cases of venous infarction is vasogenic in nature due to reduced venous drainage. An imaging study of our patient shows congestive thalamic edema and DCVT and decreased CBF in the thalamus and basal ganglia. We believe that because of the persistence of high venous and capillary pressures, ischemic change occurred in the thalamus. Like in arterial infarction, if this state continues, it might lead to complete stroke. Of 23 patients reported in the literature (Table 1), 5 presented with mild symptoms, 7 with neurologic deficits, and 11 with decline of consciousness or seizure. In all patients with DCVT, signal intensity changes were limited to one thalamus (n = 7) or both thalami (n = 16). Of all patients, 5 had mild symptoms, 17 15 australia completely recovered, and 1 had persistent deficits. In 7 patients with focal neurologic symptoms, 3 recovered almost completely. Finally, of 11 patients with impairment of consciousness or coma, 1 had persistent deficits. In 22 of 23 patients treated with heparin and warfarin, 1 patient was treated with factor Xa inhibitor (edoxaban). The patients had no relevant complications or recurrent thrombotic events. Factor Xa inhibitor was an uncommon therapy for deep venous infarction but safe and effective in our case and review case. Even in DCVT, edoxaban might be a desirable treatment alternative to vitamin K antagonists because of its known application and metabolism benefits.