Potent fibrinolysis inhibitor discovered by shape and electrostatic complementarity to the drug tranexamic acid.

Article Details

Citation

Bostrom J, Grant JA, Fjellstrom O, Thelin A, Gustafsson D

Potent fibrinolysis inhibitor discovered by shape and electrostatic complementarity to the drug tranexamic acid.

J Med Chem. 2013 Apr 25;56(8):3273-80. doi: 10.1021/jm301818g. Epub 2013 Apr 10.

PubMed ID
23521080 [ View in PubMed
]
Abstract

Protein-protein interfaces provide an important class of drug targets currently receiving increased attention. The typical design strategy to inhibit protein-protein interactions usually involves large molecules such as peptides and macrocycles. One exception is tranexamic acid (TXA), which, as a lysine mimetic, inhibits binding of plasminogen to fibrin. However, the daily dose of TXA is high due to its modest potency and pharmacokinetic properties. In this study, we report a computational approach, where the focus was on finding electrostatic potential similarities to TXA. Coupling this computational technique with a high-quality low-throughput screen identified 5-(4-piperidyl)-3-isoxazolol (4-PIOL) as a potent plasminogen binding inhibitor with the potential for the treatment of various bleeding disorders. Remarkably, 4-PIOL was found to be more than four times as potent as the drug TXA.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
Tranexamic acidPlasminogenIC 50 (nM)3100N/AN/ADetails
Tranexamic acidPlasminogenIC 50 (nM)11500N/AN/ADetails