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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Novel aryl β-aminocarbonyl derivatives as inhibitors of Trypanosoma cruzi trypanothione reductase: Binding mode revised by docking and GRIND2-based 3D-QSAR procedures
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Novel aryl β-aminocarbonyl derivatives as inhibitors of Trypanosoma cruzi trypanothione reductase: Binding mode revised by docking and GRIND2-based 3D-QSAR procedures

机译：新颖的芳基β-氨基羰基衍生物作为克氏锥虫锥虫硫醚还原酶的抑制剂：结合模式通过对接和基于GRIND2的3D-QSAR程序进行了修订

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Trypanothione reductase has long been investigated as a promising target for chemotherapeutic intervention in Chagas disease, since it is an enzyme of a unique metabolic pathway that is exclusively present in the pathogen but not in the human host, which has the analog Glutathione reductase. In spite of the present data-set includes a small number of compounds, a combined use of flexible docking, pharmacophore perception, ligand binding site prediction, and Grid-Independent Descriptors GRIND2-based 3D-Quantitative Structure-Activity Relationships (QSAR) procedures allowed us to rationalize the different biological activities of a series of 11 aryl β-aminocarbonyl derivatives, which are inhibitors of Trypanosoma cruzi trypanothione reductase (TcTR). Three QSAR models were built and validated using different alignments, which are based on docking with the TcTR crystal structure, pharmacophore, and molecular interaction fields. The high statistical significance of the models thus obtained assures the robustness of this second generation of GRIND descriptors here used, which were able to detect the most important residues of such enzyme for binding the aryl β-aminocarbonyl derivatives, besides to rationalize distances among them. Finally, a revised binding mode has been proposed for our inhibitors and independently supported by the different methodologies here used, allowing further optimization of the lead compounds with such combined structure- and ligand-based approaches in the fight against the Chagas disease.
机译：锥虫硫磷还原酶一直被研究为恰加斯病中化学疗法的有希望的靶标，因为它是一种独特的代谢途径酶，仅在病原体中存在，而在人类宿主中不存在，具有类似的谷胱甘肽还原酶。尽管目前的数据集包括少量化合物，但可以组合使用灵活的对接，药效基团感知，配体结合位点预测和基于网格独立描述符的基于GRIND2的3D定量结构-活性关系（QSAR）程序我们将一系列11种芳基β-氨基羰基衍生物的不同生物活性合理化，这些衍生物是克氏锥虫锥虫硫醚还原酶（TcTR）的抑制剂。使用与TcTR晶体结构，药效团和分子相互作用场对接的不同比对，构建并验证了三个QSAR模型。如此获得的模型的高度统计意义确保了此处使用的第二代GRIND描述子的鲁棒性，该描述子能够检测此类酶中与芳基β-氨基羰基衍生物结合的最重要残基，并能使它们之间的距离合理化。最后，已为我们的抑制剂提出了一种改良的结合模式，并得到了本文使用的不同方法的独立支持，从而可以利用这种基于结构和配体的组合方法进一步优化先导化合物，以对抗南美锥虫病。

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