硝酮与马来酰亚胺[3 + 2]环加成的机理研究:MEDT视角下的DFT、BET、对接和ADMET联合方法

IF 2.2 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY
Raghad Mowafak Al-Mokhtar, Haydar Mohammad-Salim, Muheb Algso
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引用次数: 0

摘要

利用分子电子密度理论(MEDT)在MPWB95/6-311G(d,p)水平上研究了马来酰亚胺(MD1, MD2)与硝基酮(NT1, NT2, NT3)之间的[3 + 2]环加成(32CA)反应。概念密度泛函理论(CDFT)指数分别证实了马来酰亚胺(MD1, MD2)和硝基化合物(NT1, NT2, NT3)作为亲电试剂和亲核试剂的作用。反应通过两种可能的途径进行:外链和内链。势能面(PES)的研究表明,外通路和内通路的吉布斯自由能值分别为(- 13.84,- 13.82,- 12.31,- 14.18 kcal·mol-1)和(- 8.78,- 7.87,- 7.88,- 8.54 kcal·mol-1),表明反应是动力学控制的、高度放热的自发反应,其值为负ΔG。整体电子密度转移(GEDT)值在0.08 ~ 0.19e之间,表明正向电子密度通量(FEDF)型的低极性电子密度从硝基化合物(NT1, NT2, NT3)转移到马来酰亚胺(MD1, MD2),而局部指数,特别是Parr函数,则说明了电子自旋分布。利用电子定位函数(ELF)结合分子中原子量子理论(QTAIM)进行分析,确定了硝基酮参与了一步zw型32CA反应。然而,对过渡态电子密度的拓扑分析表明,这些反应是通过非协调机制进行的。键演化理论(BET)进一步阐明了反应机理,揭示了过渡态C4-C3和C5-O1键上的6个结构稳定域(ssd)和伪自由基中心。分子对接研究表明,环合物(IZ1, IZ2, IZ3和IZ4)与密歇根癌症基金会-7 (MCF-7)蛋白(3ERT)的结合能(- 10.88,- 10.61,- 10.40和- 11.68 kcal mol-1)低于共晶配体(- 13.10 kcal mol-1)。计算机ADMET和药物相似预测显示了进一步研究的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Mechanistic study of nitrone and maleimide [3 + 2] cycloaddition: a combined DFT, BET study, docking, and ADMET approach from the MEDT perspective

A [3 + 2] cycloaddition (32CA) reaction between maleimide (MD1, MD2) and nitrones (NT1, NT2, NT3) was investigated at the MPWB95/6-311G(d,p) level of theory utilizing Molecular Electron Density Theory (MEDT). Conceptual density functional theory (CDFT) indices substantiated the roles of maleimide (MD1, MD2) and nitrones (NT1, NT2, NT3) as electrophiles and nucleophiles, respectively. The reaction proceeds via two possible pathways: exo and endo. Investigation of the Potential Energy Surface (PES) revealed that the exo and endo pathways exhibit Gibbs free energy values of (− 13.84, − 13.82, − 12.31, − 14.18 kcal·mol-1) and (− 8.78, − 7.87, − 7.88, − 8.54 kcal·mol-1), respectively, indicating kinetically controlled, highly exothermic, and spontaneous reactions, as evidenced by negative ΔG values. The global electron density transfer (GEDT) values ranging from 0.08 to 0.19e suggest a low-polarity electron density transfer of the forward electron density flux (FEDF) type from nitrones (NT1, NT2, NT3) to maleimide (MD1, MD2), while local indices, particularly Parr functions, elucidate the electronic spin distribution. Analyses employing electron localization function (ELF) in conjunction with quantum theory of atoms in molecules (QTAIM) identified the nitrone species as participating in a one-step zw-type 32CA reaction. However, topological analysis of the electron density at the transition state demonstrated that these reactions proceed via a non-concerted mechanism. Bonding Evolution Theory (BET) analysis further elucidated the reaction mechanism, revealing six Structural Stability Domains (SSDs) and pseudoradical centers at the C4–C3 and C5–O1 bonds in the transition states. Molecular docking studies demonstrated that the cycloadducts (IZ1, IZ2, IZ3, and IZ4) exhibited binding energies (− 10.88, − 10.61, − 10.40, and − 11.68 kcal mol-1) with the Michigan Cancer Foundation-7 (MCF-7) protein (3ERT) that were lower than the co-crystal ligand (− 13.10 kcal mol-1). The in silico ADMET and drug-likeness predictions suggest promising potential for further investigation.

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来源期刊
Structural Chemistry
Structural Chemistry 化学-化学综合
CiteScore
3.80
自引率
11.80%
发文量
227
审稿时长
3.7 months
期刊介绍: Structural Chemistry is an international forum for the publication of peer-reviewed original research papers that cover the condensed and gaseous states of matter and involve numerous techniques for the determination of structure and energetics, their results, and the conclusions derived from these studies. The journal overcomes the unnatural separation in the current literature among the areas of structure determination, energetics, and applications, as well as builds a bridge to other chemical disciplines. Ist comprehensive coverage encompasses broad discussion of results, observation of relationships among various properties, and the description and application of structure and energy information in all domains of chemistry. We welcome the broadest range of accounts of research in structural chemistry involving the discussion of methodologies and structures,experimental, theoretical, and computational, and their combinations. We encourage discussions of structural information collected for their chemicaland biological significance.
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