• ISSN 1674-8301
  • CN 32-1810/R
Volume 34 Issue 6
Nov.  2020
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Article Contents
Yangfang Yun, Hengyi Song, Yin Ji, Da Huo, Feng Han, Fei Li, Nan Jiang. Identification of therapeutic drugs against COVID-19 through computational investigation on drug repurposing and structural modification[J]. The Journal of Biomedical Research, 2020, 34(6): 458-469. doi: 10.7555/JBR.34.20200044
Citation: Yangfang Yun, Hengyi Song, Yin Ji, Da Huo, Feng Han, Fei Li, Nan Jiang. Identification of therapeutic drugs against COVID-19 through computational investigation on drug repurposing and structural modification[J]. The Journal of Biomedical Research, 2020, 34(6): 458-469. doi: 10.7555/JBR.34.20200044

Identification of therapeutic drugs against COVID-19 through computational investigation on drug repurposing and structural modification

doi: 10.7555/JBR.34.20200044
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  • Corresponding author: Nan Jiang, Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, 101 Longmian Avenue, Nanjing,Jiangsu 211166, China. Tel/Fax: +86-25-86868485/+86-25-86868467, E-mail: jiangnan@njmu.edu.cn
  • Received: 2020-04-01
  • Revised: 2020-06-22
  • Accepted: 2020-06-30
  • Published: 2020-08-31
  • Issue Date: 2020-11-28
  • Global prevalence of coronavirus disease 2019 (COVID-19) calls for an urgent development of anti-viral regime. Compared with the development of new drugs, drug repurposing can significantly reduce the cost, time, and safety risks. Given the fact that coronavirus harnesses spike protein to invade host cells through angiotensin-converting enzyme 2 (ACE2), hence we see if any previous anti-virtual compounds can block spike-ACE2 interaction and inhibit the virus entry. The results of molecular docking and molecular dynamic simulations revealed that remdesivir exhibits better than expected anti-viral invasion potential against COVID-19 among the three types of compounds including remdesivir, tenofovir and lopinavir. In addition, a positive correlation between the surface area occupied by remdesivir and anti-viral invasion potential was also found. As such, the structure of remdesivir was modified by linking an N-benzyl substituted diamidine derivative to its hydroxyl group through an ester bond. It was found that this compound has a higher anti-viral invasion potential and greater specificity.

     

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  • [1]
    Wang ML, Cao RY, Zhang LK, et al. remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro[J]. Cell Res,2020, 30(3): 269–271. doi: 10.1038/s41422-020-0282-0
    [2]
    Mwololo SW, Mutiso JM, Macharia JC, et al. In vitro activity and in vivo efficacy of a combination therapy of diminazene and chloroquine against murine visceral leishmaniasis[J]. J Biomed Res,2015, 29(3): 214–223. doi: 10.7555/JBR.29.20140072
    [3]
    Muralidharan N, Sakthivel R, Velmurugan D, et al. Computational studies of drug repurposing and synergism of lopinavir, oseltamivir and ritonavir binding with SARS-CoV-2 protease against COVID-19[J]. J Biomol Struct Dyn,2020. doi: 10.1080/07391102.2020.1752802. [Epub ahead of print
    [4]
    Xue XY, Yu HW, Yang HT, et al. Structures of two coronavirus main proteases: implications for substrate binding and antiviral drug design[J]. J Virol,2008, 82(5): 2515–2527. doi: 10.1128/JVI.02114-07
    [5]
    Xu XT, Chen P, Wang JF, et al. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission[J]. Sci China Life Sci,2020, 63(3): 457–460. doi: 10.1007/s11427-020-1637-5
    [6]
    Zhao D, Wang ZM, Wang LS. Prevention of atrial fibrillation with renin-angiotensin system inhibitors on essential hypertensive patients: a meta-analysis of randomized controlled trials[J]. J Biomed Res,2015, 29(6): 475–485. doi: 10.7555/JBR.29.20140149
    [7]
    Kumar Ramanathan AS, Karuppiah B, Vijayan M, et al. Effect of angiotensin converting enzyme gene I/D polymorphism in South Indian children with nephrotic syndrome[J]. J Biomed Res,2019, 33(3): 201–207. doi: 10.7555/JBR.32.20150095
    [8]
    Zhang YZ. Initial genome release of novel coronavirus[EB/OL]. [2020-01-10]. http://virological.org/t/initial-genome-release-of-novel-coronavirus/319?from=groupmessage.
    [9]
    Morse JS, Lalonde T, Xu SQ, et al. Learning from the past: possible urgent prevention and treatment options for severe acute respiratory infections caused by 2019-nCoV[J]. Chembiochem,2020, 21(5): 730–738. doi: 10.1002/cbic.202000047
    [10]
    Dong N, Yang XM, Ye LW, et al. Genomic and protein structure modelling analysis depicts the origin and infectivity of 2019-nCoV, a new coronavirus which caused a pneumonia outbreak in Wuhan, China[EB/OL]. [2020-01-21]. https://www.biorxiv.org/content/10.1101/2020.01.20.913368v1.
    [11]
    Wrapp D, Wang NS, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation[J]. Science,2020, 367(6483): 1260–1263. doi: 10.1126/science.abb2507
    [12]
    Waterhouse A, Bertoni M, Bienert S, et al. SWISS-MODEL: homology modelling of protein structures and complexes[J]. Nucleic Acids Res,2018, 46(W1): W296–W303. doi: 10.1093/nar/gky427
    [13]
    Bienert S, Waterhouse A, de Beer TAP, et al. The SWISS-MODEL Repository-new features and functionality[J]. Nucleic Acids Res,2017, 45(D1): D313–D319. doi: 10.1093/nar/gkw1132
    [14]
    Bertoni M, Kiefer F, Biasini M, et al. Modeling protein quaternary structure of homo- and hetero-oligomers beyond binary interactions by homology[J]. Sci Rep,2017, 7(1): 10480. doi: 10.1038/s41598-017-09654-8
    [15]
    Ikram S, Ahmad J, Durdagi S. Screening of FDA approved drugs for finding potential inhibitors against Granzyme B as a potent drug-repurposing target[J]. J Mol Graph Model,2020, 95: 107462. doi: 10.1016/j.jmgm.2019.107462
    [16]
    Kondagari B, Dulapalli R, Krishna Murthy D, et al. Towards the virtual screening of BIK inhibitors with the homology-modeled protein structure[J]. Med Chem Res,2013, 22(3): 1184–1196. doi: 10.1007/s00044-012-0105-z
    [17]
    Kumar S, Jena L, Mohod K, et al. Virtual screening for potential inhibitors of high-risk human papillomavirus 16 E6 protein[J]. Interdiscip Sci Comput Life Sci,2015, 7(2): 136–142. doi: 10.1007/s12539-015-0008-z
    [18]
    Umamaheswari A, Pradhan D, Hemanthkumar M. Virtual screening for potential inhibitors of homology modeled Leptospira interrogans MurD ligase[J]. J Chem Biol,2010, 3(4): 175–187. doi: 10.1007/s12154-010-0040-8
    [19]
    Tan WSD, Liao WP, Zhou S, et al. Targeting the renin-angiotensin system as novel therapeutic strategy for pulmonary diseases[J]. Curr Opin Pharmacol,2018, 40: 9–17. doi: 10.1016/j.coph.2017.12.002
    [20]
    MD simulated (37 °C, water, all-atom) model of Spike-ACE2(Spike is a homo-trimer in color, human ACE2 is in yellow)[EB/OL]. [2020-06-19]. https://ghddi-ailab.github.io/Targeting2019-nCoV/nCov_Structures/.
    [21]
    Spitzer R, Jain AN. Surflex-dock: docking benchmarks and real-world application[J]. J Comput Aided Mol Des,2012, 26(6): 687–699. doi: 10.1007/s10822-011-9533-y
    [22]
    Tripos Inc. SYBYL-X 1.3[EB/OL]. [2011-07-14]. https://sybyl-x.software.informer.com/1.3/.
    [23]
    Zhang G, Guo S, Cui HQ, et al. Virtual screening of small molecular inhibitors against DprE1[J]. Molecules,2018, 23(3): 524. doi: 10.3390/molecules23030524
    [24]
    Case DA, Betz RM, Cerutti DS, et al. AMBER 2016[CP]. San Francisco, CA: University of California, 2016.
    [25]
    Jorgensen WL, Chandrasekhar J, Madura JD. Comparison of simple potential functions for simulating liquid water[J]. J Chem Phys,1983, 79(2): 926–935. doi: 10.1063/1.445869
    [26]
    de Souza ON, Ornstein RL. Effect of periodic box size on aqueous molecular dynamics simulation of a DNA dodecamer with particle-mesh Ewald method[J]. Biophys J,1997, 72(6): 2395–2397. doi: 10.1016/S0006-3495(97)78884-2
    [27]
    Berendsen HJC, Postma JPM, van Gunsteren WF, et al. Molecular dynamics with coupling to an external bath[J]. J Chem Phys,1984, 81(8): 3684–3690. doi: 10.1063/1.448118
    [28]
    Ryckaert JP, Ciccotti G, Berendsen HJC. Numerical integration of the Cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes[J]. J Comput Phys,1977, 23(3): 327–341. doi: 10.1016/0021-9991(77)90098-5
    [29]
    Duan Y, Wu C, Chowdhury S, et al. A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations[J]. J Comput Chem,2003, 24(16): 1999–2012. doi: 10.1002/jcc.10349
    [30]
    Frisch MJ, Trucks GW, Schlegel HB, et al. Gaussian 09 (revision D.01)[CP]. Wallingford, CT: Gaussian Inc., 2009.
    [31]
    Wang JM, Wolf RM, Caldwell JW, et al. Development and testing of a general amber force field[J]. J Comput Chem,2004, 25(9): 1157–1174. doi: 10.1002/jcc.20035
    [32]
    Brice AR, Dominy BN. Analyzing the robustness of the MM/PBSA free energy calculation method: application to DNA conformational transitions[J]. J Comput Chem,2011, 32(7): 1431–1440. doi: 10.1002/jcc.21727
    [33]
    Negri M, Recanatini M, Hartmann RW. Computational investigation of the binding mode of bis(hydroxylphenyl)arenes in 17β-HSD1: molecular dynamics simulations, MM-PBSA free energy calculations, and molecular electrostatic potential maps[J]. J Comput Aided Mol Des,2011, 25(9): 795–811. doi: 10.1007/s10822-011-9464-7
    [34]
    Chéron N, Shakhnovich EI. Effect of sampling on BACE-1 ligands binding free energy predictions via MM-PBSA calculations[J]. J Comput Chem,2017, 38(22): 1941–1951. doi: 10.1002/jcc.24839
    [35]
    Li GD, de Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV)[J]. Nat Rev Drug Discov,2020, 19(3): 149–150. doi: 10.1038/d41573-020-00016-0
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