Conformers, properties, and docking mechanism of the anticancer drug docetaxel: DFT and molecular dynamics studies,Journal of Computational Chemistry

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Conformers, properties, and docking mechanism of the anticancer drug docetaxel: DFT and molecular dynamics studies
Journal of Computational Chemistry ( IF 3.4 ) Pub Date : 2018-01-12 , DOI: 10.1002/jcc.25165
Chuancai Sun ₁ , Lijuan Zhu ₁ , Chao Zhang ₁ , Ce Song _{2,

3} , Cuihong Wang ₄ , Meiling Zhang ₁ , Yaoming Xie ₅ , Henry F. Schaefer ₅

Affiliation

The conformational structures and properties of the anticancer drug docetaxel (DTX) are studied theoretically. A total of 3888 trial structures were initially generated by all combinations of internal single‐bond rotamers and screened with the B3LYP/3‐21G* method. A total of 31 unique conformers were further optimized at the B3LYP/6‐311G* method. Their relative energies, dipole moments, rotational constants, and harmonic vibrational frequencies were predicted. Single‐point relative energies were then determined at the M06‐L/6‐311G(2df,p) level. The UV spectrum of the lowest‐lying DTX conformer in methanol was investigated with the TD‐CAM‐B3LYP/6‐311 + G(2df,p) method. The 31 unique DTX structures are mainly docked at three different sites within β‐tubulin. Based on the results of molecular docking and double‐float MD simulations, the lowest‐lying DTX conformer consistently exhibits good docking performance with β‐tubulin. We identified the residues LYS299, ARG215, GLN294, LEU275, THR216, GLU290, PRO274, and THR276 on β‐tubulin as active sites forming a binding pocket responsible for locking DTX within β‐tubulin to make the combination more stable. The RMSD values show that the predicted complexes are favorable, and the SASA analysis shows that the hydrophilic properties of DTX are better than paclitaxel. © 2018 Wiley Periodicals, Inc.

中文翻译：

抗癌药物多西紫杉醇的构象物、性质和对接机制：DFT 和分子动力学研究

从理论上研究了抗癌药物多西紫杉醇（DTX）的构象结构和性质。共有 3888 个试验结构最初由内部单键旋转异构体的所有组合产生，并用 B3LYP/3-21G* 方法筛选。在 B3LYP/6-311G* 方法中进一步优化了总共 31 个独特的构象异构体。预测了它们的相对能量、偶极矩、旋转常数和谐波振动频率。然后在 M06-L/6-311G(2df,p) 水平上确定单点相对能量。使用 TD-CAM-B3LYP/6-311 + G(2df,p) 方法研究了甲醇中最低位 DTX 构象异构体的紫外光谱。31 个独特的 DTX 结构主要停靠在 β-微管蛋白内的三个不同位点。基于分子对接和双浮动 MD 模拟的结果，位于最低位置的 DTX 构象异构体始终表现出与 β-微管蛋白的良好对接性能。我们确定了 β-微管蛋白上的残基 LYS299、ARG215、GLN294、LEU275、THR216、GLU290、PRO274 和 THR276 作为活性位点，形成一个结合口袋，负责将 DTX 锁定在 β-微管蛋白内，使组合更稳定。RMSD值表明预测的复合物是有利的，SASA分析表明DTX的亲水性优于紫杉醇。© 2018 Wiley Periodicals, Inc. RMSD值表明预测的复合物是有利的，SASA分析表明DTX的亲水性优于紫杉醇。© 2018 Wiley Periodicals, Inc. RMSD值表明预测的复合物是有利的，SASA分析表明DTX的亲水性优于紫杉醇。© 2018 Wiley Periodicals, Inc.

更新日期：2018-01-12

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