Potent Fibrinolysis Inhibitor Discovered by Shape and Electrostatic Complementarity to the Drug Tranexamic Acid

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• 作者：Jonas Bostr枚m ; J. Andrew Grant ; Ola Fjellstr枚m ; Anders Thelin ; David Gustafsson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：April 25, 2013
• 年：2013
• 卷：56
• 期：8
• 页码：3273-3280
• 全文大小：388K
• 年卷期：v.56,no.8(April 25, 2013)
• ISSN：1520-4804

文摘

Protein鈥損rotein interfaces provide an important class of drug targets currently receiving increased attention. The typical design strategy to inhibit protein鈥損rotein 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.