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Computer-aided analysis of the interactions of glutamine synthetase with its inhibitors

机译：谷氨酰胺合成酶与其抑制剂相互作用的计算机辅助分析

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Mechanism of inhibition of glutamine synthetase (EC 6.3.1.2; GS) by phosphinothricin and its analogues was studied in some detail using molecular modeling methods. Among three possible conformations of phosphinothricin in the active site of GS, this compatible with binding mode of methionine sulfoximine, determined recently by crystallography, was found to be energetically favored. Basing on these results eleven inhibitors of GS were docked into its active site. Taking into consideration that phosphinothricin acts as suicide inhibitor, which is due to phosphorylation by the enzyme, seven of studied analogues were additionally analyzed in their phosphorylated forms. All the inhibitor-enzyme complexes were evaluated quantitatively by using eight scoring functions implemented in Insight and Sybyl program packages and significant correlation between the obtained scores and experimental pK_i values was achieved. Computed surface charge distribution for five selected inhibitors in both free and phosphorylated forms and their comparison with electronic structure of enzymatic reaction transition state allowed us to determine important electronic features required to construct potent inhibitors of glutamine synthetase.
机译：使用分子模拟方法详细研究了膦丝菌素及其类似物抑制谷氨酰胺合成酶（EC 6.3.1.2； GS）的机理。在GS的活性位点中，膦丝菌素的三种可能构象中，最近与晶体学确定的这种与蛋氨酸硫肟亚胺的结合模式相容，在能量学上受到了青睐。基于这些结果，将11种GS抑制剂对接至其活性位点。考虑到膦丝菌素起自杀抑制剂的作用，这是由于酶的磷酸化所致，另外还分析了七个研究的类似物的磷酸化形式。通过使用在Insight和Sybyl程序包中实现的八个评分功能，对所有抑制剂-酶复合物进行了定量评估，并获得了得分与实验pK_i值之间的显着相关性。计算的五种选定抑制剂的游离和磷酸化形式的表面电荷分布以及与酶促反应过渡态电子结构的比较，使我们能够确定构建有效的谷氨酰胺合成酶抑制剂所需的重要电子特征。

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