Theoretical analysis of the binding of iron(III) protoporphyrin IX to 4-methoxyacetophenone thiosemicarbazone via DFT-D3, MEP, QTAIM, NCI, ELF, and LOL studies
Theoretical analysis of the binding of iron(III) protoporphyrin IX to 4-methoxyacetophenone thiosemicarbazone via DFT-D3, MEP, QTAIM, NCI, ELF, and LOL studies
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DOI：
10.1007/s00894-017-3370-4
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发表时间：
2017-07-01
影响因子：
2.2
通讯作者：
Ghogomu, Julius Numbonui
中科院分区：
文献类型：
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作者：
Nkungli, Nyiang Kennet;Ghogomu, Julius Numbonui
硫代氨基脲具有多种药理特性，包括抗疟疾活性。它们的药理活性已被深入研究，但这些研究很少集中在它们的抗疟疾作用方式上。为了阐明这种抗疟机制，我们研究了铁（III）原卟啉IX （Fe(III) PPIX）与4-甲氧基苯乙酮硫代氨基脲（MAPTSC）的硫-巯基互变异构体之间相互作用的性质。本文采用了色散校正密度泛函理论（DFT-D3）、分子原子量子理论（QTAIM）、非共价相互作用指数（NCI）、电子定位函数（ELF）、定域轨道定位器（LOL）和热力学计算。Fe(III) PPIX- maptsc结合有望抑制血色素的形成，从而阻止Fe(III) PPIX在疟原虫中的解毒。利用分子静电势（MEP）图和基于dft的局部反应性指数，对MAPTSC硫-硫基互变异构体的原子结合位点进行了初步研究。MAPTSC的硫和硫互变异构体的硫离子硫和n -2-亚甲基氮/硫醇硫分别被确定为亲核攻击最有利的亲核位点。计算得到的Fe(III) PPIX-MAPTSC的结合能、焓和吉布斯自由能均为负值，表明Fe(III) PPIX-MAPTSC配合物的存在性和稳定性。MAPTSC-Fe(III) PPIX的一个丙酸侧链上NH2基团与C=O基团之间的配位键和强氢键（N-H中心点中心点中心点O）对Fe(III) PPIX-MAPTSC结合至关重要。QTAIM， NCI， ELF和LOL分析揭示了Fe(III) PPIX和MAPTSC之间微弱的非共价相互作用的微妙相互作用，主要是Fe(III) PPIX-MAPTSC复合物之间的色散样范德瓦尔斯相互作用。
Thiosemicarbazones display diverse pharmacological properties, including antimalarial activities. Their pharmacological activities have been studied in depth, but little of this research has focused on their antimalarial mode of action. To elucidate this antimalarial mechanism, we investigated the nature of the interactions between iron(III) protoporphyrin IX (Fe(III) PPIX) and the thione-thiol tautomers of 4-methoxyacetophenone thiosemicarbazone (MAPTSC). Dispersion-corrected density functional theory (DFT-D3), the quantum theory of atoms in molecules (QTAIM), the noncovalent interaction (NCI) index, the electron localization function (ELF), the localized orbital locator (LOL), and thermodynamic calculations were employed in this work. Fe(III) PPIX-MAPTSC binding is expected to inhibit hemozoin formation, thereby preventing Fe(III) PPIX detoxification in plasmodia. Preliminary studies geared toward the identification of atomic binding sites in the thione-thiol tautomers of MAPTSC were carried out using molecular electrostatic potential (MEP) maps and conceptual DFT-based local reactivity indices. The thionic sulfur and the N-2-azomethine nitrogen/thiol sulfur of, respectively, the thione and thiol tautomers of MAPTSC were identified as the most favorable nucleophilic sites for electrophilic attack. The negative values of the computed Fe(III) PPIX-MAPTSC binding energies, enthalpies, and Gibbs free energies are indicative of the existence and stability of Fe(III) PPIX-MAPTSC complexes. MAPTSC-Fe(III) coordinate bonds and strong hydrogen bonds (N-H center dot center dot center dot O) between the NH2 group in MAPTSC and the C=O group in one propionate side chain of Fe(III) PPIX are crucial to Fe(III) PPIX-MAPTSC binding. QTAIM, NCI, ELF, and LOL analyses revealed a subtle interplay of weak noncovalent interactions dominated by dispersive-like van der Waals interactions between Fe(III) PPIX and MAPTSC that stabilize the Fe(III) PPIX-MAPTSC complexes.