Computer-Aided Molecular Modeling Research Center, Kansai (CAMM-Kansai), Kobe, Japan.
J Enzyme Inhib Med Chem. 2012 Aug;27(4):571-7. doi: 10.3109/14756366.2011.603129. Epub 2011 Oct 12.
Plasmin plays important roles in various physiological systems. The identification of inhibitors controlling its regulation represents a promising drug-discovery challenge. To develop selective inhibitors of plasmin, structural information of the binding modes is crucial. Here, a computational docking study was conducted to provide structural insight into plasmin subsite interactions with substrates/inhibitors. Predicted binding modes of two peptide-substrates (D/L-Ile-Phe-Lys), and potent and weak inhibitors (YO-2 and PKSI-527) suggested non-prime and prime subsite interactions relevant to recognition by plasmin. Predicted binding modes also correlated well with the experimental structure-activity relationships for plasmin substrates/inhibitors, namely the differences of K(M) values between the D- and L-peptide-substrates and inhibitory potencies of YO-2 and PKSI-527. In particular, interaction observed at a hydrophobic pocket near S2 and at a tunnel-shaped hydrophobic S1' was strongly suggested to be significantly involved in tight binding of inhibitors to plasmin. Our present findings may aid in the design of potent and selective plasmin inhibitors.
纤溶酶在各种生理系统中发挥着重要作用。鉴定控制其调节的抑制剂代表了一个有前途的药物发现挑战。为了开发纤溶酶的选择性抑制剂，了解其结合模式的结构信息至关重要。在这里，进行了计算对接研究，以提供有关纤溶酶亚基与底物/抑制剂相互作用的结构见解。两种肽底物（D/L-异亮氨酸-苯丙氨酸-赖氨酸）和有效和弱抑制剂（YO-2 和 PKSI-527）的预测结合模式表明，非主要和主要亚基相互作用与纤溶酶的识别有关。预测的结合模式也与纤溶酶底物/抑制剂的实验构效关系很好地相关，即 D-和 L-肽底物之间 K（M）值的差异以及 YO-2 和 PKSI-527 的抑制效力。特别是，在 S2 附近的疏水口袋和隧道形疏水 S1'处观察到的相互作用强烈表明其在抑制剂与纤溶酶的紧密结合中起着重要作用。我们目前的研究结果可能有助于设计有效的和选择性的纤溶酶抑制剂。
