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新型冠状病毒(SARS-CoV-2) RNA聚合酶抑制剂的密度泛函理论计算辅助筛选
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Abstract:
瑞德西韦(Remdesivir, GS-5734)是一种在研的核苷类RNA聚合酶抑制剂，被认为是治疗新冠肺炎(COVID-19)的候选药物，现已被批准用于临床试验阶段。本文以瑞德西韦为参考，基于密度泛函理论(DFT)，对六种RNA聚合酶抑制剂进行了进一步的量子化学辅助筛选。将六种药物分子的电子结构性质与瑞德西韦进行了系统的对比，发现化合物6的偶极矩、能隙值、概念密度泛函参数均与瑞德西韦相近，因此推测该化合物也可能是一种潜在的SARS-CoV-2病毒RNA聚合酶的抑制剂。最终，通过分子对接实验进一步证实了化合物6对SARS-CoV-2 RNA聚合酶的潜在抑制能力。本文有望为候选药物的进一步筛选提供一种量子化学计算辅助手段。
Remdesivir (GS-5734) is a valuable nucleoside RNA polymerase inhibitor, which is considered to be a potential drug for curing COVID-19 and has been used in clinical trials now. In this paper, six potential RNA polymerase inhibitors were compared with Remdesivir based on the density func-tional theory (DFT). By comparing electronic structure properties of the chosen inhibitors with Remdesivir, it is found that the dipole moment, energy gap, and conceptual density functional pa-rameters of compound 6 were similar to those of Remdesivir, indicating its potential of serving as inhibitor of SARS-CoV-2 RNA polymerase. Moreover, the potential inhibitory ability of compound 6 against SARS-CoV-2 was further confirmed by molecular docking study. This paper is expected to provide a quantum chemical computation aided strategy for further screening drug candidates.
| [1] | Sheahan, T.P., Sims, A.C., Graham, R.L., et al. (2017) Broad-Spectrum Antiviral GS-5734 Inhibits Both Epidemic and Zoonotic Coronaviruses. Science Translational Medicine, 9, eaal3653. https://doi.org/10.1126/scitranslmed.aal3653 |
| [2] | Tchesnokov, E.P., Feng, J.Y., Porter, D.P., et al. (2019) Mechanism of Inhibition of Ebola Virus RNA-Dependent RNA Polymerase by Remdesivir. Viruses, 11, 326. https://doi.org/10.3390/v11040326 |
| [3] | Wang, M., Cao, R., Zhang, L., et al. (2020) Remdesivir and Chloroquine Ef-fectively Inhibit the Recently Emerged Novel Coronavirus (2019-nCoV) in Vitro. Cell Research, 30, 269-271. https://doi.org/10.1038/s41422-020-0282-0 |
| [4] | 望石智慧. 靶向RNA聚合酶核苷类化合物抑制2019-nCoV潜在应用的再发现[EB/OL].
http://www.stonewise.cn/newsinfo/2102661.html, 2020-02-06. |
| [5] | Grein, J., Ohmagari, N., Shin, D., et al. (2020) Com-passionate Use of Remdesivir for Patients with Severe Covid-19. New England Journal of Medicine, 1-10. https://doi.org/10.1056/NEJMoa2007016 |
| [6] | Miertus, S. and Tomasi, J. (1982) Approximate Evaluations of the Elec-trostatic Free Energy and Internal Energy Changes in Solution Processes. Chemical Physics, 65, 239-245. https://doi.org/10.1016/0301-0104(82)85072-6 |
| [7] | Miertu？, S., Scrocco, E. and Tomasi, J. (1981) Electrostatic Inte-raction of a Solute with a Continuum. A Direct Utilizaion of AB Initio Molecular Potentials for the Prevision of Solvent Effects. Chemical Physics, 55, 117-129.
https://doi.org/10.1016/0301-0104(81)85090-2 |
| [8] | Frisch, M.J., Trucks, G.W., Schlegel, H. B., et al. (2016) Gaussian 16, Revision A.03. Gaussian, Inc., Wallingford. |
| [9] | Dennington, R., Keith, T. and Millam, J.G. (2016) GaussView, Version 6. Semichem Inc., Shawnee Mission. |
| [10] | Lu, T. and Chen, F. (2012) Multiwfn: A Multifunctional Wavefunction Analyzer. Journal of Computational Chemistry, 33, 580-592. https://doi.org/10.1002/jcc.22885 |
| [11] | Humphrey, W., Dalke, A., Schulten, K., et al. (1996) VMD: Visual Molecular Dynamics. Journal of Molecular Graphics, 14, 33-38. https://doi.org/10.1016/0263-7855(96)00018-5 |
| [12] | Kuruvilla, T.K., Prasana, J.C., Muthu, S., et al. (2018) Quantum Mechanical and Spectroscopic (FT-IR, FT-Raman) Study, NBO Analysis, HOMO-LUMO, First Order Hyperpolarizability and Molecular Docking Study of Methyl[(3R)-3-(2-methylphenoxy)-3-phenylpropyl]amine by Density Functional Method. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 188, 382-393. https://doi.org/10.1016/j.saa.2017.07.029 |
| [13] | Mutter, S.T. and Platts, J.A. (2011) Density Functional Theory Studies of Interactions of Ruthenium-Arene Complexes with Base Pair Steps. The Journal of Physical Chemistry A, 115, 11293-11302. https://doi.org/10.1021/jp2049487 |
| [14] | Streitwieser, A. (2013) Molecular Orbital Theory for Organic Chemists. In: Pioneers of Quantum Chemistry, American Chemical Society, Washington DC, 275-300. https://doi.org/10.1021/bk-2013-1122.ch009 |
| [15] | Hutama, A.S., Huang, H. and Kurniawan, Y.S. (2019) Investigation of the Chemical and Optical Properties of Halogen-Substituted N-methyl-4-piperidone Curcumin Analogs by Density Functional Theory Calculations. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 221, Article ID: 117152.
https://doi.org/10.1016/j.saa.2019.117152 |
| [16] | Parr, R.G., Donnelly, R.A., Levy, M., et al. (1978) Electronegativity: The Density Functional Viewpoint. The Journal of Chemical Physics, 68, 3801-3807. https://doi.org/10.1063/1.436185 |
| [17] | Parr, R.G., Szentpaly, L.V. and Liu, S. (1999) Electrophilicity Index. Chemical Reviews, 121, 1922-1924.
https://doi.org/10.1021/ja983494x |
| [18] | Badrinarayan, P. and Narahari Sastry, G. (2011) Virtual High Throughput Screening in New Lead Identification. Combinatorial Chemistry & High Throughput Screening, 14, 840-860. https://doi.org/10.2174/138620711797537102 |
| [19] | Kitchen, D.B., Decornez, H., Furr, J.R., et al. (2004) Docking and Scoring in Virtual Screening for Drug Discovery: Methods and Applications. Nature Reviews Drug Discovery, 3, 935-949. https://doi.org/10.1038/nrd1549 |
| [20] | Kellenberger, E., Rodrigo, J., Muller, P., et al. (2004) Comparative Evaluation of Eight Docking Tools for Docking and Virtual Screening Accuracy. Proteins, 57, 225-242. https://doi.org/10.1002/prot.20149 |
| [21] | Jain, A.N. (2004) Ligand-Based Structural Hypotheses for Virtual Screening. Journal of Medicinal Chemistry, 47, 947-961. https://doi.org/10.1021/jm030520f |
| [22] | Cleves, A.E. and Jain, A.N. (2006) Robust Ligand-Based Modeling of the Biological Targets of Known Drugs. Journal of Medicinal Chemistry, 49, 2921-2938. https://doi.org/10.1021/jm051139t |
| [23] | 冀树伸, 黄新安, 罗荣华, 等. 分子对接技术筛选抗HIV-1逆转录酶活性化合物[J]. 广州中医药大学学报, 2015, 4(4): 725-728. |
