Potent Fibrinolysis Inhibitor Discovered by Shape and Electrostatic Complementarity to the Drug Tranexamic Acid
Potent Fibrinolysis Inhibitor Discovered by Shape and Electrostatic Complementarity to the Drug Tranexamic Acid
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DOI：
10.1021/jm301818g
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发表时间：
2013-04-25
影响因子：
7.3
通讯作者：
Gustafsson, David
中科院分区：
文献类型：
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作者：
Bostrom, Jonas;Grant, J. Andrew;Gustafsson, David
蛋白质-蛋白质界面提供了一类重要的药物靶点，目前正受到越来越多的关注。抑制蛋白质相互作用的典型设计策略通常涉及大分子，如肽和大环化合物。一个例外是氨甲环酸（TXA），其作为赖氨酸模拟物，抑制纤溶酶原与纤维蛋白的结合。然而，TXA的日剂量由于其适度的效力和药代动力学性质而很高。在这项研究中，我们报告了一种计算方法，其重点是寻找静电势与TXA的相似性。将这种计算技术与高质量低通量筛选相结合，鉴定了5-（4-哌啶基）-3-异恶唑醇（4-PIOL）作为有效的纤溶酶原结合抑制剂，具有治疗各种出血性疾病的潜力。值得注意的是，发现4-PIOL的效力是药物TXA的四倍多。
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.