Docking Simulations Exhibit Bortezomib and other Boron-containing Peptidomimetics as Potential Inhibitors of SARS-CoV-2 Main Protease

Author(s): Iván R Vega-Valdez, Rosalez Melvin N., Santiago-Quintana José M., Farfán-García Eunice D., Soriano-Ursúa Marvin A.*

Journal Name: Current Chemical Biology

Volume 14 , Issue 4 , 2020


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Graphical Abstract:


Abstract:

Background: Treatment of the COVID19 pandemic requires drug development. Boron- containing compounds are attractive chemical agents, some of them act as proteases inhibitors.

Objective: The present study explores the role of boronic moieties in molecules interacting on the binding site of the SARS-CoV-2 main protease.

Methods: Conventional docking procedure was applied by assaying boron-free and boron-containing compounds on the recently reported crystal structure of SARS-CoV-2 main protease (PDB code: 6LU7). The set of 150 ligands includes bortezomib and inhibitors of coronavirus proteases.

Results: Most of the tested compounds share contact with key residues and pose on the cleavage pocket. The compounds with a boron atom in their structure are often estimated to have higher affinity than boron-free analogues.

Conclusion: Interactions and the affinity of boron-containing peptidomimetics strongly suggest that boron-moieties increase affinity on the main protease, which is tested by in vitro assays. A Bis-boron-containing compound previously tested active on SARS-virus protease and bortezomib were identified as potent ligands. These advances may be relevant to drug designing, in addition to testing available boron-containing drugs in patients with COVID19 infection.

Keywords: Boron, boronic acids, oligopeptides, bortezomib, protease inhibitors, COVID19.

[1]
Soriano-Ursúa MA, Das BC, Trujillo-Ferrara JG. Boron-containing compounds: chemico-biological properties and expanding medicinal potential in prevention, diagnosis and therapy. Expert Opin Ther Pat 2014; 24(5): 485-500.
[http://dx.doi.org/10.1517/13543776.2014.881472] [PMID: 24456081]
[2]
Ban HS, Nakamura H. Boron-based drug design. Chem Rec 2015; 15(3): 616-35.
[http://dx.doi.org/10.1002/tcr.201402100] [PMID: 25800654]
[3]
Fernandes GFS, Denny WA, Dos Santos JL. Boron in drug design: Recent advances in the development of new therapeutic agents. Eur J Med Chem 2019; 179: 791-804.
[http://dx.doi.org/10.1016/j.ejmech.2019.06.092] [PMID: 31288128]
[4]
Farfán-García ED, Castillo-Mendieta NT, Ciprés-Flores FJ, Padilla-Martínez II, Trujillo-Ferrara JG, Soriano-Ursúa MA. Current data regarding the structure-toxicity relationship of boron-containing compounds. Toxicol Lett 2016; 258: 115-25.
[http://dx.doi.org/10.1016/j.toxlet.2016.06.018] [PMID: 27329537]
[5]
Soriano-Ursúa MA, Farfán-García ED, Geninatti-Crich S. Turning fear of boron toxicity into boron-containing drug design. Curr Med Chem 2019; 26: 5005-18.
[http://dx.doi.org/10.2174/0929867326666190327154954] [PMID: 30919770]
[6]
Nocentini A, Supuran CT, Winum J-Y. Benzoxaborole compounds for therapeutic uses: a patent review (2010- 2018). Expert Opin Ther Pat 2018; 28(6): 493-504.
[http://dx.doi.org/10.1080/13543776.2018.1473379] [PMID: 29727210]
[7]
Krajnc A, Lang PA, Panduwawala TD, Brem J, Schofield CJ. Will morphing boron-based inhibitors beat the β-lactamases? Curr Opin Chem Biol 2019; 50: 101-10.
[http://dx.doi.org/10.1016/j.cbpa.2019.03.001] [PMID: 31004962]
[8]
Ghosh AK, Xia Z, Kovela S, et al. Potent HIV-1 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein-Ligand X-ray Structural Studies. ChemMedChem 2019; 14(21): 1863-72.
[http://dx.doi.org/10.1002/cmdc.201900508] [PMID: 31549492]
[9]
Windsor IW, Palte MJ, Lukesh JC III, Gold B, Forest KT, Raines RT. Sub-picomolar Inhibition of HIV-1 Protease with a Boronic Acid. J Am Chem Soc 2018; 140(43): 14015-8.
[http://dx.doi.org/10.1021/jacs.8b07366] [PMID: 30346745]
[10]
Nitsche C, Zhang L, Weigel LF, et al. Peptide-Boronic Acid Inhibitors of Flaviviral Proteases: Medicinal Chemistry and Structural Biology. J Med Chem 2017; 60(1): 511-6.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01021] [PMID: 27966962]
[11]
Meo SA, Alhowikan AM, Al-Khlaiwi T, et al. Novel coronavirus 2019-nCoV: prevalence, biological and clinical characteristics comparison with SARS-CoV and MERS-CoV. Eur Rev Med Pharmacol Sci 2020; 24(4): 2012-9.
[PMID: 32141570]
[12]
Tuite AR, Bogoch I, Sherbo R, et al. Estimation of COVID-2019 burden and potential for international dissemination of infection from Iran. Ann Intern Med 2020.
[http://dx.doi.org/10.7326/M20-0696] [PMID: 32176272]
[13]
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395(10229): 1054-62.
[http://dx.doi.org/10.1016/S0140-6736(20)30566-3] [PMID: 32171076]
[14]
Li H, Wang YM, Xu JY, Cao B. Potential antiviral therapeutics for 2019 Novel Coronavirus. Zhonghua Jie He He Hu Xi Za Zhi 2020; 43: E0002.
[15]
Fan H-H, Wang L-Q, Liu W-L, et al. Repurposing of clinically approved drugs for treatment of coronavirus disease 2019 in a 2019-novel coronavirus-related coronavirus model. Chin Med J (Engl) 2020; 133(9): 1051-6.
[http://dx.doi.org/10.1097/CM9.0000000000000797] [PMID: 32149769]
[16]
Morse JS, Lalonde T, Xu S, Liu WR. Learning from the Past: Possible Urgent Prevention and Treatment Options for Severe Acute Respiratory Infections Caused by 2019-nCoV. ChemBioChem 2020; 21(5): 730-8.
[http://dx.doi.org/10.1002/cbic.202000047] [PMID: 32022370]
[17]
Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020; 367(6483): 1260-3.
[http://dx.doi.org/10.1126/science.abb2507] [PMID: 32075877]
[18]
Liu W, Zhu H-L, Duan Y. Effective Chemicals against Novel Coronavirus (COVID-19) in China. Curr Top Med Chem 2020; 20(8): 603-5.
[http://dx.doi.org/10.2174/1568026620999200305145032] [PMID: 32133962]
[19]
Dong S, Sun J, Mao Z, Wang L, Lu YL, Li J. A guideline for homology modeling of the proteins from newly discovered betacoronavirus, 2019 novel coronavirus (2019-nCoV). J Med Virol 2020.
[http://dx.doi.org/10.1002/jmv.25768] [PMID: 32181901]
[20]
Schrader J, Henneberg F, Mata RA, et al. The inhibition mechanism of human 20S proteasomes enables next-generation inhibitor design. Science 2016; 353(6299): 594-8.
[http://dx.doi.org/10.1126/science.aaf8993] [PMID: 27493187]
[21]
Xi J, Zhuang R, Kong L, He R, Zhu H, Zhang J. Immunoproteasome-selective inhibitors: An overview of recent developments as potential drugs for hematologic malignancies and autoimmune diseases. Eur J Med Chem 2019; 182: 111646.
[http://dx.doi.org/10.1016/j.ejmech.2019.111646] [PMID: 31521028]
[22]
Colland F. The therapeutic potential of deubiquitinating enzyme inhibitors. Biochem Soc Trans 2010; 38(Pt 1): 137-43.
[http://dx.doi.org/10.1042/BST0380137] [PMID: 20074048]
[23]
Liu S, Liu H, Zhang K, et al. Proteasome Inhibitor PS-341 Effectively Blocks Infection by the Severe Fever with Thrombocytopenia Syndrome Virus. Virol Sin 2019; 34(5): 572-82.
[http://dx.doi.org/10.1007/s12250-019-00162-9] [PMID: 31637631]
[24]
Shahiduzzaman M, Ezatti P, Xin G, Coombs KM. Proteasomal serine hydrolases are up-regulated by and required for influenza virus infection. J Proteome Res 2014; 13(5): 2223-38.
[http://dx.doi.org/10.1021/pr5001779] [PMID: 24669782]
[25]
Dai Y, Peralta AN, Wynn JE, et al. Molecular recognition of a branched peptide with HIV-1 Rev Response Element (RRE) RNA. Bioorg Med Chem 2019; 27(8): 1759-65.
[http://dx.doi.org/10.1016/j.bmc.2019.03.016] [PMID: 30879859]
[26]
Ton A-T, Gentile F, Hsing M, Ban F, Cherkasov A. Rapid Identification of Potential Inhibitors of SARS-CoV-2 Main Protease by Deep Docking of 1.3 Billion Compounds. Mol Inform 2020; 39(8): e2000028.
[http://dx.doi.org/10.1002/minf.202000028] [PMID: 32162456]
[27]
García AA, Rayevski A, Andrade-Jorge E, Trujillo-Ferrara JG. Structural and biological overview of Boron-containing amino acids in the medicinal chemistry field. Curr Med Chem 2018; 26: 5077-89.
[http://dx.doi.org/10.2174/0929867325666180926150403] [PMID: 30259808]
[28]
Bacha U, Barrila J, Velazquez-Campoy A, Leavitt SA, Freire E. Identification of novel inhibitors of the SARS coronavirus main protease 3CLpro. Biochemistry 2004; 43(17): 4906-12.
[http://dx.doi.org/10.1021/bi0361766] [PMID: 15109248]
[29]
Reille S, Garnier M, Robert X, Gouet P, Martin J, Launay G. Identification and visualization of protein binding regions with the ArDock server. Nucleic Acids Res 2018; 46(W1): W417-22.
[http://dx.doi.org/10.1093/nar/gky472] [PMID: 29905873]
[30]
Jendele L, Krivak R, Skoda P, Novotny M, Hoksza D. PrankWeb: a web server for ligand binding site prediction and visualization. Nucleic Acids Res 2019; 47(W1): W345-9.
[http://dx.doi.org/10.1093/nar/gkz424] [PMID: 31114880]
[31]
Morris GM, Huey R, Lindstrom W, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 2009; 30(16): 2785-91.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[32]
Huey R, Morris GM, Olson AJ, Goodsell DS. A semiempirical free energy force field with charge-based desolvation. J Comput Chem 2007; 28(6): 1145-52.
[http://dx.doi.org/10.1002/jcc.20634] [PMID: 17274016]
[33]
Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph 1996; 14(1): 33-38, 27-28.
[http://dx.doi.org/10.1016/0263-7855(96)00018-5] [PMID: 8744570]
[34]
Pillaiyar T, Manickam M, Namasivayam V, Hayashi Y, Jung SH. An overview of severe acute respiratory syndrome-coronavirus (SARS-CoV) 3CL protease inhibitors: Peptidomimetics and small molecule chemotherapy. J Med Chem 2016; 59(14): 6595-628.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01461] [PMID: 26878082]
[35]
Anand K, Ziebuhr J, Wadhwani P, Mesters JR, Hilgenfeld R. Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs. Science 2003; 300(5626): 1763-7.
[http://dx.doi.org/10.1126/science.1085658] [PMID: 12746549]
[36]
Kiemer L, Lund O, Brunak S, Blom N. Coronavirus 3CLpro proteinase cleavage sites: possible relevance to SARS virus pathology. BMC Bioinformatics 2004; 5: 72.
[http://dx.doi.org/10.1186/1471-2105-5-72] [PMID: 15180906]
[37]
Jin Z, Du X, Xu Y, et al. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature 2020; 582(7811): 289-93.
[http://dx.doi.org/10.1038/s41586-020-2223-y] [PMID: 32272481]
[38]
Zhou J, Fang L, Yang Z, et al. Identification of novel proteolytically inactive mutations in coronavirus 3C-like protease using a combined approach. FASEB J 2019; 33(12): 14575-87.
[http://dx.doi.org/10.1096/fj.201901624RR] [PMID: 31690127]
[39]
Bandi P, Garcia ML, Booth CJ, Chisari FV, Robek MD. Bortezomib inhibits hepatitis B virus replication in transgenic mice. Antimicrob Agents Chemother 2010; 54(2): 749-56.
[http://dx.doi.org/10.1128/AAC.01101-09] [PMID: 19949053]
[40]
Ma X-Z, Bartczak A, Zhang J, et al. Proteasome inhibition in vivo promotes survival in a lethal murine model of severe acute respiratory syndrome. J Virol 2010; 84(23): 12419-28.
[http://dx.doi.org/10.1128/JVI.01219-10] [PMID: 20861244]
[41]
Longhitano L, Tibullo D, Giallongo C, et al. Proteasome Inhibitors as a Possible Therapy for SARS--CoV-2. Int J Mol Sci 2020; 21(10): 3622.
[http://dx.doi.org/10.3390/ijms21103622] [PMID: 32443911]
[42]
Venkatraman S, Wu W, Prongay A, Girijavallabhan V, George Njoroge F. Potent inhibitors of HCV-NS3 protease derived from boronic acids. Bioorg Med Chem Lett 2009; 19(1): 180-3.
[http://dx.doi.org/10.1016/j.bmcl.2008.10.124] [PMID: 19022670]
[43]
Soriano-Ursúa MA, Arias-Montaño JA, Correa-Basurto J, et al. Insights on the role of boron containing moieties in the design of new potent and efficient agonists targeting the β2 adrenoceptor. Bioorg Med Chem Lett 2015; 25(4): 820-5.
[http://dx.doi.org/10.1016/j.bmcl.2014.12.077] [PMID: 25592716]
[44]
Soriano-Ursúa MA, Bello M, Hernández-Martínez CF, et al. Cell-based assays and molecular dynamics analysis of a boron-containing agonist with different profiles of binding to human and guinea pig beta2 adrenoceptors. Eur Biophys J 2019; 48(1): 83-97.
[http://dx.doi.org/10.1007/s00249-018-1336-9] [PMID: 30386878]
[45]
Basler M, Lauer C, Beck U, Groettrup M. The proteasome inhibitor bortezomib enhances the susceptibility to viral infection. J Immunol 2009; 183(10): 6145-50.
[http://dx.doi.org/10.4049/jimmunol.0901596] [PMID: 19841190]
[46]
Yanaba K, Yoshizaki A, Muroi E, et al. The proteasome inhibitor bortezomib inhibits T cell-dependent inflammatory responses. J Leukoc Biol 2010; 88(1): 117-22.
[http://dx.doi.org/10.1189/jlb.1009666] [PMID: 20418448]
[47]
Schneider SM, Pritchard SM, Wudiri GA, Trammell CE, Nicola AV. Early steps in herpes simplex virus infection blocked by a proteasome inhibitor. MBio 2019; 10(3): e00732-19.
[http://dx.doi.org/10.1128/mBio.00732-19] [PMID: 31088925]
[48]
Lv BM, Tong XY, Quan Y, et al. Drug repurposing for Japanese encephalitis virus infection by systems biology methods. Molecules 2018; 23(12): 3346.
[http://dx.doi.org/10.3390/molecules23123346] [PMID: 30567313]
[49]
Barrows NJ, Campos RK, Powell ST, et al. A Screen of FDA-Approved Drugs for Inhibitors of Zika Virus Infection. Cell Host Microbe 2016; 20(2): 259-70.
[http://dx.doi.org/10.1016/j.chom.2016.07.004] [PMID: 27476412]
[50]
Raaben M, Grinwis GCM, Rottier PJM, de Haan CAM. The proteasome inhibitor Velcade enhances rather than reduces disease in mouse hepatitis coronavirus-infected mice. J Virol 2010; 84(15): 7880-5.
[http://dx.doi.org/10.1128/JVI.00486-10] [PMID: 20484516]
[51]
Schneider M, Ackermann K, Stuart M, et al. Severe acute respiratory syndrome coronavirus replication is severely impaired by MG132 due to proteasome-independent inhibition of M-calpain. J Virol 2012; 86(18): 10112-22.
[http://dx.doi.org/10.1128/JVI.01001-12] [PMID: 22787216]
[52]
Raaben M, Posthuma CC, Verheije MH, et al. The ubiquitin-proteasome system plays an important role during various stages of the coronavirus infection cycle. J Virol 2010; 84(15): 7869-79.
[http://dx.doi.org/10.1128/JVI.00485-10] [PMID: 20484504]
[53]
Natesampillai S, Cummins NW, Nie Z, et al. HIV Protease-Generated Casp8p41, When Bound and Inactivated by Bcl2, Is Degraded by the Proteasome. J Virol 2018; 92(13): e00037-18.
[http://dx.doi.org/10.1128/JVI.00037-18] [PMID: 29643240]
[54]
Ganguly S, Kuravi S, Alleboina S, et al. Targeted Therapy for EBV-Associated B-cell Neoplasms. Mol Cancer Res 2019; 17(4): 839-44.
[http://dx.doi.org/10.1158/1541-7786.MCR-18-0924] [PMID: 30487243]
[55]
Vogl DT, Martin TG, Vij R, et al. Phase I/II study of the novel proteasome inhibitor delanzomib (CEP-18770) for relapsed and refractory multiple myeloma. Leuk Lymphoma 2017; 58(8): 1872-9.
[http://dx.doi.org/10.1080/10428194.2016.1263842] [PMID: 28140719]


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Article Details

VOLUME: 14
ISSUE: 4
Year: 2020
Page: [279 - 288]
Pages: 10
DOI: 10.2174/2212796814999201102195651

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