Potent fibrinolysis inhibitor discovered by shape and electrostatic complementarity to the drug tranexamic Acid.
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.
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CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-Y GENE-N GENE-Y
tranexamic acid TXA lysine TXA TXA 5-(4-piperidyl)-3-isoxazolol 4-PIOL 4-PIOL TXA tranexamic Acid plasminogen fibrin plasminogen