Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods
Canrong Wu, Yang Liu, Yueying Yang, Peng Zhang, Wu Zhong, Yali Wang, Qiqi Wang, Yang Xu, Mingxue Li, Xingzhou Li, Mengzhu Zheng, Lixia Chen, Hua Li, Canrong Wu, Yang Liu, Yueying Yang, Peng Zhang, Wu Zhong, Yali Wang, Qiqi Wang, Yang Xu, Mingxue Li, Xingzhou Li, Mengzhu Zheng, Lixia Chen, Hua Li
Abstract
SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths. There are currently no registered therapies for treating coronavirus infections. Because of time consuming process of new drug development, drug repositioning may be the only solution to the epidemic of sudden infectious diseases. We systematically analyzed all the proteins encoded by SARS-CoV-2 genes, compared them with proteins from other coronaviruses, predicted their structures, and built 19 structures that could be done by homology modeling. By performing target-based virtual ligand screening, a total of 21 targets (including two human targets) were screened against compound libraries including ZINC drug database and our own database of natural products. Structure and screening results of important targets such as 3-chymotrypsin-like protease (3CLpro), Spike, RNA-dependent RNA polymerase (RdRp), and papain like protease (PLpro) were discussed in detail. In addition, a database of 78 commonly used anti-viral drugs including those currently on the market and undergoing clinical trials for SARS-CoV-2 was constructed. Possible targets of these compounds and potential drugs acting on a certain target were predicted. This study will provide new lead compounds and targets for further in vitro and in vivo studies of SARS-CoV-2, new insights for those drugs currently ongoing clinical studies, and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.
Keywords: 3CLpro, 3-chymotrypsin-like protease; Drug repurposing; E, envelope; Homology modeling; M, membrane protein; Molecular docking; N, nucleocapsid protein; Nsp, non-structure protein; ORF, open reading frame; PDB, protein data bank; RdRp, RNA-Dependence RNA polymerase; Remdesivir; S, Spike; SARS-CoV-2; SUD, SARS unique domain; UB, ubiquitin-like domain.
© 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
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References
- Cheng V.C., Lau S.K., Woo P.C., Yuen K.Y. Severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection. Clin Microbiol Rev. 2007;20:660–694.
- Lee N., Hui D., Wu A., Chan P., Cameron P., Joynt G.M. A major outbreak of severe acute respiratory syndrome in Hong Kong. N Engl J Med. 2003;348:1986–1994.
- Zaki A.M., van Boheemen S., Bestebroer T.M., Osterhaus A.D., Fouchier R.A. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med. 2012;367:1814–1820.
- de Groot R.J., Baker S.C., Baric R.S., Brown C.S., Drosten C., Enjuanes L. Middle East respiratory syndrome coronavirus (MERS-CoV): announcement of the Coronavirus Study Group. J Virol. 2013;87:7790–7792.
- Lau S.K., Woo P.C., Li K.S., Huang Y., Tsoi H.-W., Wong B.H.L. Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats. Proc Natl Acad Sci U S A. 2005;102:14040–14045.
- Reusken C.B., Haagmans B.L., Müller M.A., Gutierrez C., Godeke G.-J., Meyer B. El Tahir YE, De Sousa R, van Beek J, Nowotny N, van Maanen K, Hidalgo-Hermoso E, Bosch B-J, Rottier P, Osterhaus A, Gortázar-Schmidt C, Drosten C, Koopmans MPG. Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study. Lancet Infect Dis. 2013;13:859–866.
- Zhu N., Zhang D., Wang W., Li X., Yang B., Song J. China Novel Coronavirus I, Research T. A novel coronavirus from patients with pneumonia in China. N Engl J Med. 2020;382:727–733.
- Chen Y., Liu Q., Guo D. Emerging coronaviruses: genome structure, replication, and pathogenesis. J Med Virol. 2020;92:418–423.
- Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet. 2020;395:497–506.
- Bosch B.J., van der Zee R., de Haan C.A., Rottier P.J. The coronavirus spike protein is a class I virus fusion protein: structural and functional characterization of the fusion core complex. J Virol. 2003;77:8801–8811.
- Omrani A.S., Saad M.M., Baig K., Bahloul A., Abdul-Matin M., Alaidaroos A.Y. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. Lancet Infect Dis. 2014;14:1090–1095.
- Ge X.Y., Li J.L., Yang X.L., Chmura A.A., Zhu G., Epstein J.H. Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature. 2013;503:535–538.
- Han D.P., Penn-Nicholson A., Cho M.W. Identification of critical determinants on ACE2 for SARS-CoV entry and development of a potent entry inhibitor. Virology. 2006;350:15–25.
- Li W., Moore M.J., Vasilieva N., Sui J., Wong S.K., Berne M.A. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426:450–454.
- Zhao J., Li K., Wohlford-Lenane C., Agnihothram S.S., Fett C., Zhao J. Rapid generation of a mouse model for Middle East respiratory syndrome. Proc Natl Acad Sci U S A. 2014;111:4970–4975.
- Agrawal A.S., Garron T., Tao X., Peng B.H., Wakamiya M., Chan T.S. Generation of a transgenic mouse model of Middle East respiratory syndrome coronavirus infection and disease. J Virol. 2015;89:3659–3670.
- Zumla A., Chan J.F., Azhar E.I., Hui D.S., Yuen K.Y. Coronaviruses—drug discovery and therapeutic options. Nat Rev Drug Discov. 2016;15:327–347.
- Chan J.F., Chan K.H., Kao R.Y., To K.K., Zheng B.J., Li C.P.Y. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J Infect. 2013;67:606–616.
- de Wilde A.H., Jochmans D., Posthuma C.C., Zevenhoven-Dobbe J.C., van Nieuwkoop S., Bestebroer T.M. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East Respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother. 2014;14:4875–4884.
- Dyall J., Coleman C.M., Hart B.J., Venkataraman T., Holbrook M.R., Kindrachuk J. Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother. 2014;58:4885–4893.
- Jaroszewski L., Rychlewski L., Li Z., Li W., Godzik A. FFAS03: a server for profile–profile sequence alignments. Nucleic Acids Res. 2005;33:W284–W288.
- Irwin J.J., Sterling T., Mysinger M.M., Bolstad E.S., Coleman R.G. ZINC: a free tool to discover chemistry for biology. J Chem Inf Model. 2012;52:1757–1768.
- Abagyan R., Totrov M., Kuznetsov D. ICM—A new method for protein modeling and design: applications to docking and structure prediction from the distorted native conformation. J Comput Chem. 1994;15:488–506.
- Wan Y., Shang J., Graham R., Baric R.S., Li F. Receptor recognition by novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS. J Virol. 2020;94:e00127–20.
- Xu X., Chen P., Wang J., Feng J., Zhou H., Li X. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Sci China Life Sci. 2020;63:457–460.
- Li F., Li W., Farzan M., Harrison S.C. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science. 2005;309:1864–1868.
- Harcourt B.H., Jukneliene D., Kanjanahaluethai A., Bechill J., Severson K.M., Smith C.M. Identification of severe acute respiratory syndrome coronavirus replicase products and characterization of papain-like protease activity. J Virol. 2004;78:13600–13612.
- Chen X., Yang X., Zheng Y., Yang Y., Xing Y., Chen Z. SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING–TRAF3–TBK1 complex. Protein Cell. 2014;5:369–381.
- Yuan L., Chen Z., Song S., Wang S., Tian C., Xing G. p53 degradation by a coronavirus papain-like protease suppresses type I interferon signaling. J Biol Chem. 2015;290:3172–3182.
- Li S.W., Wang C.Y., Jou Y.J., Huang S.H., Hsiao L.H., Wan L. SARS coronavirus papain-like protease inhibits the TLR7 signaling pathway through removing Lys63-linked polyubiquitination of TRAF3 and TRAF6. Int J Mol Sci. 2016;17:678.
- Yang H., Xie W., Xue X., Yang K., Ma J., Liang W. Design of wide-spectrum inhibitors targeting coronavirus main proteases. PLoS Biol. 2005;3:e324.
- Pillaiyar T., Manickam M., Namasivayam V., Hayashi Y., Jung S.H. An overview of severe acute respiratory syndrome-coronavirus (SARS-CoV) 3CL protease inhibitors: peptidomimetics and small molecule chemotherapy. J Med Chem. 2016;59:6595–6628.
- Yang H., Yang M., Ding Y., Liu Y., Lou Z., Zhou Z. The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor. Proc Natl Acad Sci U S A. 2003;100:13190–13195.
- Subissi L., Imbert I., Ferron F., Collet A., Coutard B., Decroly E. SARS-CoV ORF1b-encoded nonstructural proteins 12–16: replicative enzymes as antiviral targets. Antiviral Res. 2014;101:122–130.
- Imbert I., Guillemot J.C., Bourhis J.M., Bussetta C., Coutard B., Egloff M.-P. A second, non-canonical RNA-dependent RNA polymerase in SARS coronavirus. EMBO J. 2006;25:4933–4942.
- Chu C.K., Gadthula S., Chen X., Choo H., Olgen S., Barnard D.L. Antiviral activity of nucleoside analogues against SARS-coronavirus (SARS-CoV) Antivir Chem Chemother. 2006;17:285–289.
- Ivanov K.A., Ziebuhr J. Human coronavirus 229E nonstructural protein 13: characterization of duplex-unwinding, nucleoside triphosphatase, and RNA 5′-triphosphatase activities. J Virol. 2004;78:7833–7838.
- Shum K.T., Tanner J.A. Differential inhibitory activities and stabilisation of DNA aptamers against the SARS coronavirus helicase. Chembiochem. 2008;9:3037–3045.
- Jang K.J., Lee N.R., Yeo W.S., Jeong Y.J., Kim D.E. Isolation of inhibitory RNA aptamers against severe acute respiratory syndrome (SARS) coronavirus NTPase/Helicase. Biochem Biophys Res Commun. 2008;366:738–744.
- Millet J.K., Whittaker G.R. Host cell proteases: critical determinants of coronavirus tropism and pathogenesis. Virus Res. 2015;202:120–134.
- Xia S., Liu Q., Wang Q., Sun Z., Su S., Du L. Middle East respiratory syndrome coronavirus (MERS-CoV) entry inhibitors targeting spike protein. Virus Res. 2014;194:200–210.
- Kamitani W., Narayanan K., Huang C., Lokugamage K., Ikegami T., Ito N. Severe acute respiratory syndrome coronavirus nsp1 protein suppresses host gene expression by promoting host mRNA degradation. Proc Natl Acad Sci U S A. 2006;103:12885–12890.
- Narayanan K., Huang C., Lokugamage K., Kamitani W., Ikegami T., Tseng C.T.K. Severe acute respiratory syndrome coronavirus nsp1 suppresses host gene expression, including that of type I interferon, in infected cells. J Virol. 2008;82:4471–4479.
- Forni D., Cagliani R., Mozzi A., Pozzoli U., Al-Daghri N., Clerici M., Sironi M. Extensive positive selection drives the evolution of nonstructural proteins in lineage C betacoronaviruses. J Virol. 2016;90:3627–3639.
- Taylor J.K., Coleman C.M., Postel S., Sisk J.M., Bernbaum J.G., Venkataraman T. Severe acute respiratory syndrome coronavirus ORF7a inhibits bone marrow stromal antigen 2 virion tethering through a novel mechanism of glycosylation interference. J Virol. 2015;89:11820–11833.
- Glowacka I., Bertram S., Muller M.A., Allen P., Soilleux E., Pfefferle S. Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. J Virol. 2011;85:4122–4134.
- Holshue M.L., De Bolt C., Lindquist S., Lofy K.H., Wiesman J., Bruce H. Washington State 2019-nCoV Case Investigation Team. First case of 2019 novel coronavirus in the United States. N Engl J Med. 2020;382:929–936.
- Wang M., Cao R., Zhang L., Yang X., Liu J., Xu M. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30:269–271.
- van der Linden L., Vives-Adrián L., Selisko B., Ferrer-Orta C., Liu X., Lanke K. The RNA template channel of the RNA dependent RNA polymerase as a target for development of antiviral therapy of multiple genera within a virus family. PLoS Pathog. 2015;11:e1004733.
- Muegge I., Martin Y.C. A general and fast scoring function for protein ligand interactions: a simplified potential approach. J Med Chem. 1999;42:791–804.
- Neves M.A., Totrov M., Abagyan R. Docking and scoring with ICM: thebenchmarking results and strategies for improvement. J Comput Aided Mol Des. 2012;26:675–686.
- Guan W.J., Ni Z.Y., Hu Y., Liang W.H., Ou C.Q., He J.X. Clinical characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020;382:1708–1720.
- Chen H., Du Q. Potential natural compounds for preventing 2019-nCoV infection. Preprints. 2020
- Ye R., Liu Z. ACE2 exhibits protective effects against LPS-induced acute lung injury in mice by inhibiting the LPS-TLR4 pathway. Exp Mol Pathol. 2019;113:104350.
- Heald-Sargent T., Gallagher I. Ready. Set, Fuse! The coronavirus spike protein and acquisition of fusion competence. Viruses. 2012;4:557–580.
Source: PubMed