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  • Title: In silico discovery of a compound with nanomolar affinity to antithrombin causing partial activation and increased heparin affinity.
    Author: Navarro-Fernández J, Pérez-Sánchez H, Martínez-Martínez I, Meliciani I, Guerrero JA, Vicente V, Corral J, Wenzel W.
    Journal: J Med Chem; 2012 Jul 26; 55(14):6403-12. PubMed ID: 22742452.
    Abstract:
    The medical and socioeconomic relevance of thromboembolic disorders promotes an ongoing effort to develop new anticoagulants. Heparin is widely used as activator of antithrombin but incurs side effects. We screened a large database in silico to find alternative molecules and predicted d-myo-inositol 3,4,5,6-tetrakisphosphate (TMI) to strongly interact with antithrombin. Isothermal titration calorimetry confirmed a TMI affinity of 45 nM, higher than the heparin affinity (273 nM). Functional studies, fluorescence analysis, and citrullination experiments revealed that TMI induced a partial activation of antithrombin that facilitated the interaction with heparin and low affinity heparins. TMI improved antithrombin inhibitory function of plasma from homozygous patients with antithrombin deficiency with a heparin binding defect and also in a model with endothelial cells. Our in silico screen identified a new, non-polysaccharide scaffold able to interact with the heparin binding domain of antithrombin. The functional consequences of this interaction were experimentally characterized and suggest potential anticoagulant therapeutic applications.
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