耐多药结核病治疗药物及潜在药物的结构和性质计算

doi:10.3969/j.issn.2095-9400.2021.06.006

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摘要目的：比较分析耐多药结核病（MDR-TB）临床治疗药物和潜在药物结构与性质差异，为开发新药提供参考。方法：运用密度泛函理论M06-2X/6-311+G（2d，p）方法，对噁唑烷酮类MDR-TB治疗药物利奈唑胺（Lin），临床试验药物舒特唑胺（Sut）、德帕唑胺（Del）、TBI-223（223）及新近合成化合物19c的药效构象、几何和电子结构、红外（IR）、紫外-可见（UV-Vis）、电子圆二色（ECD）谱进行计算比较，并借助概念密度泛函理论进行分子全局反应指数分析，使用药物代谢动力学平台开展成药性和ADME/Tox评估。结果：计算显示19c增加一个手性中心明显减少了药效构象，在不同溶剂环境中，五种化合物药效结构几何参数值相近，计算值与晶体参数吻合较好。极性环境使Del极性改变最大。计算红外光谱特征与实验吻合。Lin计算的紫外最大吸收波数与实验完全一致，Del紫外吸收光谱以HOMO电子向LUMO跃迁为主，其他均以HOMO向LUMO+2跃迁为主，都具有双峰曲线。Sut计算ECD峰与实验相吻合。19c、Sut和Lin静电势分布主要集中在噁唑烷酮端，而Del和223则另一端呈电势负性。五种化合物反应指数彼此数值接近。类药性评价显示Del分布系数与其他差别大，整体彼此相近。动力学参数五种化合物比较一致，但临床用药Lin的参数更优。结论：新化合物19c较MDR-TB临床治疗药物及临床试验药物具有优势，存在进一步开发的价值。

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	李震岳
	翁约约
	黄罗仪
	王朝杰

关键词 ：耐多药结核病, 利奈唑胺, 密度泛函理论, 反应指数

Abstract：Objective: To compare the differences in the structures and properties of clinical drug and potential drugs for treatment multidrug-resistant tuberculosis (MDR-TB) so as to provide a reference for the development of new drugs. Methods: The pharmacophoric conformation, geometric and electronic structures, IR, UV-Vis and ECD spectra for Linezolid (Lin), the current treatment of MDR-TB and clinical trials of Sutezolid (Sut), Delpazolid (Del), TBI-223 (223), and the newly synthesized compound 19c in oxazolidinone derivatives were calculated and compared by using density functional theory M06-2X/6-311+G (2d, p). The molecular global reactivity index analysis was carried out with the aid of conceptual density functional theory, and the pharmacodynamic platform was used to calculate ADME/Tox and evaluate the druggability. Results: The data showed that the addition of a chiral center in 19c greatly reduced the pharmacophoric conformation. In different solvent environments, the geometric parameters of the pharmacophoric core in the five compounds were basically the same, and the calculated bond length values were in good agreement with the crystal parameters. Polar solvent environment caused maximum polarity change of Del. The calculated characteristics of infrared were in agreement with the experimental measurements. The theoretical maximum wavenumber of UV-Vis absorption of Lin was exactly the same as the experiment. Except that the UV-Vis absorption spectrum of Del transited from HOMO electron to LUMO, the others were HOMO→LUMO+2 transition, and all UV-Vis spectra were twin-peak curves. The ECD spectrum calculated of Sut coincided with the experiment. The electrostatic potential distribution of 19c, Sut and Lin were mainly concentrated at the oxazolidinone end, while the Del and 223 were negative at the other end. The reactivity index of the five compounds was close to each other. Drug evaluation showed that the distribution coefficient of Del was different from others, and the whole was similar to each other. Pharmacokinetic parameters of 5 compounds were consistent, but the parameters of clinical drug Lin were better. Conclusion: The new compound 19c has more advantages over clinical treatment drug and clinical trial drugs for MDR-TB, and has greater value for development.

Key words： multidrug-resistant tuberculosis linezolid density functional theory index

收稿日期: 2021-02-15

基金资助:国家自然科学基金资助项目（21177098）；浙江省自然科学基金资助项目（LY16B070006）；浙江省中医药科技计划项目（2020ZB141）；温州市基础性科研项目（Y2020191）。

通讯作者: 王朝杰，副教授，Email：chjwang@wmu.edu.cn。 E-mail: chjwang@wmu.edu.cn

作者简介: 李震岳，主管药师，Email：21719907@qq.com。

链接本文:

https://xb.wmu.edu.cn/CN/10.3969/j.issn.2095-9400.2021.06.006 或 https://xb.wmu.edu.cn/CN/Y2021/V51/I6/459

参考文献：
[1] World Health Organization. Global tuberculosis report 2020[R/OL]. Geneva: World Health Organization, 2020. https://apps.who.int/iris/handle/10665/336069.
[2] 时翠林, 牛广豪, 王霞芳, 等. 耐药结核病治疗药物研究进展[J]. 中华结核和呼吸杂志, 2020, 43(1): 58-63.
[3] 赵杰, 阚全程, 迟春花, 等. 肺结核基层合理用药指南[J]. 中华全科医师杂志, 2020, 19(10): 891-899.
[4] 周夏袷, 田文广. 耐药结核病的现状与治疗策略[J]. 西部医学, 2017, 29(1): 141-144.
[5] ZHAO H Y, WANG B, FU L, et al. Discovery of a conformationally constrained oxazolidinone with improved safety and efficacy profiles for the treatment of multidrug-resistant tuberculosis[J]. J Med Chem, 2020, 63(17): 9316-9339.
[6] KEAM S J. Pretomanid: first approval[J]. Drugs, 2019, 79(16): 1797-1803.
[7] BARBACHYN M R, HUTCHINSON D K, BRICKNER S J, et al. Identification of a novel oxazolidinone (U-100480) with potent antimycobacterial activity[J]. J Med Chem, 1996, 39(3): 680-685.
[8] JEONG J W, JUNG S J, LEE H H, et al. In vitro and in vivo activities of LCB01-0371, a new oxazolidinone[J]. Antimicrob Agents Chemother, 2010, 54(12): 5359-5362.
[9] Global alliance for TB drug development. A phase 1 Study to evaluate safety, tolerability, and pharmacokinetics of TBI-223 in healthy adults[EB/OL].(2018-11-29)[2021-05-12]. https://clinicaltrials.gov/ct2/show/NCT03758612.
[10] MARDIROSSIAN N, GORDON M H. How accurate are the minnesota density functionals for noncovalent interactions, isomerization energies, thermochemistry, and barrier heights involving molecules composed of main-group elements?[J]. J Chem Theory Comput, 2016, 12(9): 4303-4325.
[11] PARR R, YANG W. Density-functional theory of atoms and molecules[M]. New York: Oxford University Press, 1989: 102-142.
[12] CHERMETTE H. Chemical reactivity indexes in density functional theory[J]. J Comput Chem, 1999, 20(1): 129-154.
[13] GEERLINGS P, DEPROFT F, LANGENAEKER W. Conceptual density functional theory[J]. Chem Rev, 2003, 103(5): 1793-1873.
[14] LU T, CHEN F. Multiwfn: A multifunctional wavefunction analyzer[J]. J Comput Chem, 2012, 33(5): 580-592.
[15] MICHALSKA K, BOCIAN W, BEDNAREK E, et al. Enantioselective recognition of sutezolid by cyclodextrin modifiednon-aqueous capillary electrophoresis and explanation of complexformation by means of infrared spectroscopy, NMR and molecular modelling[J]. J Pharm Biomed Anal, 2019, 169: 49-59.
[16] MICHALSKA K, LEWANDOWSKA K, MIZERA M, et al. Spectroscopic identification of intermediates and final products of the chiral pool synthesis of sutezolid[J]. J Mol Struct, 2020, 1217: 128396.
[17] TOMCZAK S, STAWNY M, DETTLAFF K, et al. Physicochemical compatibility and stability of linezolid with parenteral nutrition[J]. Molecules, 2019, 24(7): 1242.
[18] KOKILAMBIGAI K S, LAKSHMI K S, SUSMITHA A S, et al. Linezolid—a review of analytical methods in pharmaceuticals and biological matrices[J]. Crit Rev Anal Chem, 2020, 50(2): 179-188.
[19] FRELEK J, GORECKI M, LASZCZ M, et al. Distinguishing between polymorphic forms of linezolid by solid-phase electronic and vibrational circular dichroism[J]. Chem Commun, 2012, 48(43): 5295-5297.
[20] 郭宗儒. 药物分子设计的策略: 药理活性与成药性[J]. 药学学报, 2010, 45(5): 539-547.
[21] ELMELIEGY M, VOURVAHIS M, GUO C C, et al. Effect of P-glycoprotein (P-gp) inducers on exposure of P-gp substrates: Review of clinical drug-drug interaction studies [J]. Clini Pharmacokinet, 2020, 59(6): 699-714.
[22] 黎迎, 朱春燕. Caco-2细胞单层模型构建及3种药物吸收机制评价[J]. 聊城大学学报, 2019, 32(4): 1-5.
[23] DECLEVES X, JACOB A, YOUSIF S. Interplay of drug metabolizing CYP450 enzymes and ABC transporters in the blood-brain barrier[J]. Curr Drug Metab, 2011, 12(8): 732-741.