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J Med Chem. 2012 Jul 26;55(14):6403-12. doi: 10.1021/jm300621j. Epub 2012 Jul 17.

In silico discovery of a compound with nanomolar affinity to antithrombin causing partial activation and increased heparin affinity.

Author information

1
Servicio de Hematología y Oncología Médica, H. U. Morales Meseguer, Centro Regional de Hemodonación, University of Murcia, Spain.

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.

PMID:
22742452
DOI:
10.1021/jm300621j
[Indexed for MEDLINE]

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