title: In silico discovery of a compound with nanomolar affinity to antithrombin causing partial activation and increased heparin affinity.
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.
authors: Servicio de Hematología y Oncología Médica, H. U. Morales Meseguer, Centro Regional de Hemodonación, University of Murcia, Spain.
authors: J
authors: J
authors: Navarro-Fernández
authors: H
authors: H
authors: Pérez-Sánchez
authors: I
authors: I
authors: Martínez-Martínez
authors: I
authors: I
authors: Meliciani
authors: J A
authors: JA
authors: Guerrero
authors: V
authors: V
authors: Vicente
authors: J
authors: J
authors: Corral
authors: W
authors: W
authors: Wenzel
mesh_terms: D000991:Antithrombins / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D019295:Computational Biology; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism* / Q000494:pharmacology*; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D015203:Reproducibility of Results
chemical_list: D000991:Antithrombins; C490694:D-myo-inositol 3,4,5,6-tetrakisphosphate; D007295:Inositol Phosphates; D006493:Heparin