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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Homology modeling and docking mechanism of the mercaptosuccinate and methotrexate to P. falciparum 1-Cys peroxiredoxin: a preliminary molecular study.
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Homology modeling and docking mechanism of the mercaptosuccinate and methotrexate to P. falciparum 1-Cys peroxiredoxin: a preliminary molecular study.

机译：巯基琥珀酸酯和甲氨蝶呤与恶性疟原虫1-半胱氨酸过氧化物酶的同源性建模和对接机理：初步的分子研究。

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摘要

A three-dimensional (3-D) model of 1-Cys peroxiredoxin from P. falciparum (Pf-Prx) has been constructed by homology modeling. The model building was based on a structural alignment with the human 1-Cys peroxiredoxin ray structure. First, mercaptosuccinate was docked by Molecular and Quantum Mechanics at the active site in both isozymes, evidencing the role of different residues in the ligand-protein interaction. Stable conformation of the inhibitor in the active site was obtained from the conformational analysis by molecular dynamics. Next, The complex was reoptimized by semiempirical molecular orbital AM1 method. Conformational and frontier orbitals analyses of the ligand-protein complex were carried out in an attempt to obtain structural insight into the inhibition mechanism. Finally, the docking study of the methotrexate (MTX), an anticancer drug also used as an antimalarial inhibitor, into the modes binding site was performed. From the resulting stable complex structure, it was found that the glutamate ring of MTX fits the active site with high complementarity. The glutamate ring formed two hydrogen bonds to the imidazol group of His41 and the amino groups of Arg129. The side-chain of glutamate was in close proximity to the sulfur atom of the catalytic residue, Cys47. This binding mode suggests a possible inhibition mechanism, whereby the cysteine residue is covered with the glutamate ring of the MTX inhibitor, forming an enzyme-ligand adduct. In addition, the higher interaction energies and the molecular orbitals localization between the Pf-Prx active site and the inhibitors alluded to the probable binding sites of the ligand nucleophilic ring.
机译：通过同源性建模，构建了恶性疟原虫1-Cys过氧化物酶的三维（3-D）模型（Pf-Prx）。该模型的建立基于与人的1-Cys过氧化物酶毒素射线结构的结构比对。首先，巯基琥珀酸酯通过分子和量子力学在两个同工酶的活性位点对接，证明了不同残基在配体-蛋白质相互作用中的作用。通过分子动力学从构象分析获得活性位点中抑制剂的稳定构象。接下来，通过半经验分子轨道AM1方法对复合物进行了优化。进行了配体-蛋白质复合物的构象和前沿轨道分析，以试图获得抑制机制的结构见解。最后，进行了甲氨蝶呤（MTX）（一种也用作抗疟疾抑制剂的抗癌药物）对接模式结合位点的研究。从得到的稳定的复杂结构中发现，MTX的谷氨酸环适合于具有高互补性的活性位点。谷氨酸环与His41的咪唑基和Arg129的氨基形成两个氢键。谷氨酸的侧链非常靠近催化残基Cys47的硫原子。该结合模式表明可能的抑制机制，其中半胱氨酸残基被MTX抑制剂的谷氨酸环覆盖，形成酶-配体加合物。此外，Pf-Prx活性位点与抑制剂之间较高的相互作用能和分子轨道定位暗示了配体亲核环的可能结合位点。

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