Structural Bioinformatics Used to Predict the Protein Targets of
Remdesivir and Flavones in SARS-CoV-2 Infection

Avram       Speranta; Laura       Manoliu; Catalina       Sogor; Maria       Mernea; Corina    Duda    Seiman; Daniel    Duda    Seiman; Carmen       Chifiriuc
doi:10.2174/1573406417666210806154129
Abstract

Background: During the current SARS-CoV-2 pandemic, the identification of effective antiviral drugs is crucial. Unfortunately, no specific treatment or vaccine is available to date.
Objective: Here, we aimed to predict the interactions with SARS-CoV-2 proteins and protein targets from the human body for some flavone molecules (kaempferol, morin, pectolinarin, myricitrin, and herbacetin) in comparison to synthetic compounds (hydroxychloroquine, remdesivir, ribavirin, ritonavir, AMD-070, favipiravir).
Methods: Using MOE software and advanced bioinformatics and cheminformatics portals, we conducted an extensive analysis based on various structural and functional features of compounds, such as their amphiphilic field, flexibility, and steric features. The structural similarity analysis of natural and synthetic compounds was performed using Tanimoto coefficients. The interactions of some compounds with SARS-CoV-2 3CLprotease or RNA-dependent RNA polymerase were described using 2D protein-ligand interaction diagrams based on known crystal structures. The potential targets of considered compounds were identified using the SwissTargetPrediction web tool.
Results: Our results showed that remdesivir, pectolinarin, and ritonavir present a strong structural similarity which may be correlated to their similar biological activity. As common molecular targets of compounds in the human body, ritonavir, kaempferol, morin, and herbacetin can activate multidrug resistance-associated proteins, while remdesivir, ribavirin, and pectolinarin appear as ligands for adenosine receptors.
Conclusion: Our evaluation recommends remdesivir, pectolinarin, and ritonavir as promising anti- SARS-CoV-2 agents.
Keywords: SARS-CoV-2, flavones, remdesivir, molecular features, target prediction, structural biology.
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[1] 
Worldometer - Real time world statistics. Available from:  https://www.worldometers.info/
                    accessed Jul 7, 2020.
[2] 
Chen, L.; Liu, W.; Zhang, Q.; Xu, K.; Ye, G.; Wu, W.; Sun, Z.; Liu, F.; Wu, K.; Zhong, B.; Mei, Y.; Zhang, W.; Chen, Y.; Li, Y.; Shi, M.; Lan, K.; Liu, Y. RNA based mNGS approach identifies a novel human coronavirus from two individual pneumonia cases in 2019 Wuhan outbreak. Emerg. Microbes Infect.,  2020, 9(1), 313-319.
[http://dx.doi.org/10.1080/22221751.2020.1725399] [PMID:  32020836] 
[3] 
Khailany, R.A.; Safdar, M.; Ozaslan, M. Genomic characterization of a novel SARS-CoV-2. Gene Rep.,  2020, 19100682
[http://dx.doi.org/10.1016/j.genrep.2020.100682] [PMID:  32300673] 
[4] 
Phan, T. Genetic diversity and evolution of SARS-CoV-2. Infect. Genet. Evol.,  2020, 81104260
[http://dx.doi.org/10.1016/j.meegid.2020.104260] [PMID:  32092483] 
[5] 
Yoshimoto, F.K. The proteins of severe acute respiratory syndrome coronavirus-2 (SARS CoV-2 or n-COV19), the cause of COVID-19. Protein J.,  2020, 39(3), 198-216.
[http://dx.doi.org/10.1007/s10930-020-09901-4] [PMID:  32447571] 
[6] 
Tahir Ul Qamar, M.; Alqahtani, S.M.; Alamri, M.A.; Chen, L.L. Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants. J. Pharm. Anal.,  2020, 10(4), 313-319.
[http://dx.doi.org/10.1016/j.jpha.2020.03.009] [PMID:  32296570] 
[7] 
Rut, W.; Lv, Z.; Zmudzinski, M.; Patchett, S.; Nayak, D.; Snipas, S.J.; El Oualid, F.; Huang, T.T.; Bekes, M.; Drag, M.; Olsen, S.K. Activity profiling and crystal structures of inhibitor-bound SARS-CoV-2 papain-like protease: A framework for anti-COVID-19 drug design. Sci. Adv.,  2020, 6(42)eabd4596
[http://dx.doi.org/10.1126/sciadv.abd4596] [PMID:  33067239] 
[8] 
Wu, C.; Liu, Y.; Yang, Y.; Zhang, P.; Zhong, W.; Wang, Y.; Wang, Q.; Xu, Y.; Li, M.; Li, X.; Zheng, M.; Chen, L.; Li, H. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm. Sin. B,  2020, 10(5), 766-788.
[http://dx.doi.org/10.1016/j.apsb.2020.02.008] [PMID:  32292689] 
[9] 
Ortega, J.T.; Serrano, M.L.; Pujol, F.H.; Rangel, H.R. Unrevealing sequence and structural features of novel coronavirus using in silico approaches: The main protease as molecular target. EXCLI J.,  2020, 19, 400-409.
[PMID:  32210741] 
[10] 
Chen, Y.W.; Yiu, C.B.; Wong, K.Y. Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL pro) structure: Virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates. F1000 Res.,  2020, 9, 129.
[http://dx.doi.org/10.12688/f1000research.22457.2] [PMID:  32194944] 
[11] 
Kumar, S.; Sharma, P.P.; Shankar, U.; Kumar, D.; Joshi, S.K.; Pena, L.; Durvasula, R.; Kumar, A.; Kempaiah, P. Poonam, discovery of new hydroxyethylamine analogs against 3CLpro protein target of SARS-CoV-2: molecular docking, molecular dynamics simulation and structure-activity relationship studies. J. Chem. Inf. Model.,  2020, 60(12), 5754-5770.
[http://dx.doi.org/10.1021/acs.jcim.0c00326] 
[12] 
Pillay, T.S. Gene of the month: The 2019-nCoV/SARS-CoV-2 novel coronavirus spike protein. J. Clin. Pathol.,  2020, 73(7), 366-369.
[http://dx.doi.org/10.1136/jclinpath-2020-206658] [PMID:  32376714] 
[13] 
Wang, M.; Cao, R.; Zhang, L.; Yang, X.; Liu, J.; Xu, M.; Shi, Z.; Hu, Z.; Zhong, W.; Xiao, G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res.,  2020, 30(3), 269-271.
[http://dx.doi.org/10.1038/s41422-020-0282-0] [PMID:  32020029] 
[14] 
Dong, L.; Hu, S.; Gao, J. Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discov. Ther.,  2020, 14(1), 58-60.
[http://dx.doi.org/10.5582/ddt.2020.01012] [PMID:  32147628] 
[15] 
Zhou, Y.; Hou, Y.; Shen, J.; Huang, Y.; Martin, W.; Cheng, F. Network-based drug repurposing for novel coronavirus 2019-NCoV/SARS-CoV-2. Cell Discov.,  2020, 6, 14.
[http://dx.doi.org/10.1038/s41421-020-0153-3] 
[16] 
Huynh, T.; Wang, H.; Luan, B. In silico exploration of the molecular mechanism of clinically oriented drugs for possibly inhibiting SARS-CoV-2's main protease. J. Phys. Chem. Lett.,  2020, 11(11), 4413-4420.
[http://dx.doi.org/10.1021/acs.jpclett.0c00994] [PMID:  32406687] 
[17] 
Cai, Q.; Yang, M.; Liu, D.; Chen, J.; Shu, D.; Xia, J.; Liao, X.; Gu, Y.; Cai, Q.; Yang, Y.; Shen, C.; Li, X.; Peng, L.; Huang, D.; Zhang, J.; Zhang, S.; Wang, F.; Liu, J.; Chen, L.; Chen, S.; Wang, Z.; Zhang, Z.; Cao, R.; Zhong, W.; Liu, Y.; Liu, L. Experimental treatment with favipiravir for COVID-19: An open-label control study. Engineering (Beijing),  2020, 6(10), 1192-1198.
[http://dx.doi.org/10.1016/j.eng.2020.03.007] [PMID:  32346491] 
[18] 
Yang, Y.; Islam, M.S.; Wang, J.; Li, Y.; Chen, X. Traditional chinese medicine in the treatment of patients infected with 2019-new coronavirus (SARS-CoV-2): A review and perspective. Int. J. Biol. Sci.,  2020, 16(10), 1708-1717.
[http://dx.doi.org/10.7150/ijbs.45538] [PMID:  32226288] 
[19] 
Heo, Y.; Cho, Y.; Ju, K.S.; Cho, H.; Park, K.H.; Choi, H.; Yoon, J.K.; Moon, C.; Kim, Y.B. Antiviral activity of Poncirus trifoliata seed extract against oseltamivir-resistant influenza virus. J. Microbiol.,  2018, 56(8), 586-592.
[http://dx.doi.org/10.1007/s12275-018-8222-0] [PMID:  30047088] 
[20] 
Wang, Q.; Wu, J.; Wang, H.; Gao, Y.; Liu, Q.; Mu, A.; Ji, W.; Yan, L.; Zhu, Y.; Zhu, C.; Fang, X.; Yang, X.; Huang, Y.; Gao, H.; Liu, F.; Ge, J.; Sun, Q.; Yang, X.; Xu, W.; Liu, Z.; Yang, H.; Lou, Z.; Jiang, B.; Guddat, L.W.; Gong, P.; Rao, Z. Structural basis for RNA replication by the SARS-CoV-2 polymerase. Cell,  2020, 182(2), 417-428.e13.
[http://dx.doi.org/10.1016/j.cell.2020.05.034] [PMID:  32526208] 
[21] 
Yao, X.; Ye, F.; Zhang, M.; Cui, C.; Huang, B.; Niu, P.; Liu, X.; Zhao, L.; Dong, E.; Song, C.; Zhan, S.; Lu, R.; Li, H.; Tan, W.; Liu, D. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin. Infect. Dis.,  2020, 71(15), 732-739.
[http://dx.doi.org/10.1093/cid/ciaa237] [PMID:  32150618] 
[22] 
Liu, J.; Cao, R.; Xu, M.; Wang, X.; Zhang, H.; Hu, H.; Li, Y.; Hu, Z.; Zhong, W.; Wang, M. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov.,  2020, 6(1), 16.
[http://dx.doi.org/10.1038/s41421-020-0156-0] [PMID:  33731711] 
[23] 
Fantini, J.; Di Scala, C.; Chahinian, H.; Yahi, N. Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection. Int. J. Antimicrob. Agents,  2020, 55(5)105960
[http://dx.doi.org/10.1016/j.ijantimicag.2020.105960] [PMID:  32251731] 
[24] 
Nimgampalle, M.; Devanathan, V.; Saxena, A. Screening of Chloroquine, Hydroxychloroquine and its derivatives for their binding affinity to multiple SARS-CoV-2 protein drug targets. J. Biomol. Struct. Dyn.,  2020, 1-13.
[http://dx.doi.org/10.1080/07391102.2020.1782265] [PMID:  32579059] 
[25] 
Ingraham, N.E.; Boulware, D.; Sparks, M.A.; Schacker, T.; Benson, B.; Sparks, J.A.; Murray, T.; Connett, J.; Chipman, J.G.; Charles, A.; Tignanelli, C.J. Shining a light on the evidence for hydroxychloroquine in SARS-CoV-2. Crit. Care,  2020, 24(1), 182.
[http://dx.doi.org/10.1186/s13054-020-02894-7] [PMID:  32345336] 
[26] 
Pruijssers, A.J.; George, A.S.; Schäfer, A.; Leist, S.R.; Gralinksi, L.E.; Dinnon, K.H., III; Yount, B.L.; Agostini, M.L.; Stevens, L.J.; Chappell, J.D.; Lu, X.; Hughes, T.M.; Gully, K.; Martinez, D.R.; Brown, A.J.; Graham, R.L.; Perry, J.K.; Du Pont, V.; Pitts, J.; Ma, B.; Babusis, D.; Murakami, E.; Feng, J.Y.; Bilello, J.P.; Porter, D.P.; Cihlar, T.; Baric, R.S.; Denison, M.R.; Sheahan, T.P. Remdesivir inhibits SARS-CoV-2 in human lung cells and chimeric SARS-CoV expressing the SARS-CoV-2 RNA polymerase in mice. Cell Rep.,  2020, 32(3)107940
[http://dx.doi.org/10.1016/j.celrep.2020.107940] [PMID:  32668216] 
[27] 
Gordon, C.J.; Tchesnokov, E.P.; Woolner, E.; Perry, J.K.; Feng, J.Y.; Porter, D.P.; Götte, M. Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. J. Biol. Chem.,  2020, 295(20), 6785-6797.
[http://dx.doi.org/10.1074/jbc.RA120.013679] [PMID:  32284326] 
[28] 
Cox, B.D.; Prosser, A.R.; Katzman, B.M.; Alcaraz, A.A.; Liotta, D.C.; Wilson, L.J.; Snyder, J.P. Anti-HIV small-molecule binding in the peptide subpocket of the CXCR4:CVX15 crystal structure. ChemBioChem,  2014, 15(11), 1614-1620.
[http://dx.doi.org/10.1002/cbic.201402056] [PMID:  24990206] 
[29] 
Jo, S.; Kim, S.; Shin, D.H.; Kim, M.S. Inhibition of SARS-CoV 3CL protease by flavonoids. J. Enzyme Inhib. Med. Chem.,  2020, 35(1), 145-151.
[http://dx.doi.org/10.1080/14756366.2019.1690480] [PMID:  31724441] 
[30] 
Tahir Ul Qamar, M.; Saleem, S.; Ashfaq, U.A.; Bari, A.; Anwar, F.; Alqahtani, S. Epitope-based peptide vaccine design and target site depiction against Middle East Respiratory Syndrome Coronavirus: An immune-informatics study. J. Transl. Med.,  2019, 17(1), 362.
[http://dx.doi.org/10.1186/s12967-019-2116-8] [PMID:  31703698] 
[31] 
Kar, P.; Sharma, N.R.; Singh, B.; Sen, A.; Roy, A. Natural compounds from Clerodendrum spp. as possible therapeutic candidates against SARS-CoV-2: An in silico investigation. J. Biomol. Struct. Dyn.,  2020, 1-12.
[http://dx.doi.org/10.1080/07391102.2020.1780947] [PMID:  32552595] 
[32] 
Khan, M.T.; Ali, A.; Wang, Q.; Irfan, M.; Khan, A.; Zeb, M.T.; Zhang, Y.J.; Chinnasamy, S.; Wei, D.Q. Marine natural compounds as potents inhibitors against the main protease of SARS-CoV-2-a molecular dynamic study. J. Biomol. Struct. Dyn.,  2020, 1-11.
[http://dx.doi.org/10.1080/07391102.2020.1769733] [PMID:  32410504] 
[33] 
Theoharides, T.C. COVID-19, pulmonary mast cells, cytokine storms, and beneficial actions of luteolin. Biofactors,  2020, 46(3), 306-308.
[http://dx.doi.org/10.1002/biof.1633] [PMID:  32339387] 
[34] 
Silva, J.K.R.D.; Figueiredo, P.L.B.; Byler, K.G.; Setzer, W.N. Essential oils as antiviral agents. potential of essential oils to treat SARS-CoV-2 infection: An in-silico investigation. Int. J. Mol. Sci.,  2020, 21(10), 3426.
[http://dx.doi.org/10.3390/ijms21103426] [PMID:  32408699] 
[35] 
Chattopadhyay, D.; Naik, T.N. Antivirals of ethnomedicinal origin: Structure-activity relationship and scope. Mini Rev. Med. Chem.,  2007, 7(3), 275-301.
[http://dx.doi.org/10.2174/138955707780059844] [PMID:  17346219] 
[36] 
Tsang, N.Y.; Zhao, L-H.; Tsang, S.W.; Zhang, H-J. Antiviral activity and molecular targets of plant natural products against avian influenza virus. Curr. Org. Chem.,  2017, 21(18), 1777-1804.
[http://dx.doi.org/10.2174/1385272821666170227120138] 
[37] 
Schwarz, S.; Sauter, D.; Wang, K.; Zhang, R.; Sun, B.; Karioti, A.; Bilia, A.R.; Efferth, T.; Schwarz, W. Kaempferol derivatives as antiviral drugs against the 3a channel protein of coronavirus. Planta Med.,  2014, 80(2-3), 177-182.
[http://dx.doi.org/10.1055/s-0033-1360277] [PMID:  24458263] 
[38] 
Hamza, M.; Ali, A.; Khan, S.; Ahmed, S.; Attique, Z.; Ur Rehman, S.; Khan, A.; Ali, H.; Rizwan, M.; Munir, A.; Khan, A.M.; Siddique, F.; Mehmood, A.; Nouroz, F.; Khan, S. nCOV-19 peptides mass fingerprinting identification, binding, and blocking of inhibitors flavonoids and anthraquinone of Moringa oleifera and hydroxychloroquine. J. Biomol. Struct. Dyn.,  2020, 1-11.
[http://dx.doi.org/10.1080/07391102.2020.1778534] [PMID:  32567487] 
[39] 
Khan, S.A.; Zia, K.; Ashraf, S.; Uddin, R.; Ul-Haq, Z. Identification of chymotrypsin-like protease inhibitors of SARS-CoV-2 via integrated computational approach. J. Biomol. Struct. Dyn.,  2020, 1-10.
[http://dx.doi.org/10.1080/07391102.2020.1751298] [PMID:  32238094] 
[40] 
Huang, Y.F.; Bai, C.; He, F.; Xie, Y.; Zhou, H. Review on the potential action mechanisms of Chinese medicines in treating Coronavirus Disease 2019 (COVID-19). Pharmacol. Res.,  2020, 158104939
[http://dx.doi.org/10.1016/j.phrs.2020.104939] [PMID:  32445956] 
[41] 
Tarasova, O.; Ivanov, S.; Filimonov, D.A.; Poroikov, V. Data and text mining help identify key proteins involved in the molecular mechanisms shared by SARS-CoV-2 and HIV-1. Molecules,  2020, 25(12), 2944.
[http://dx.doi.org/10.3390/molecules25122944] [PMID:  32604797] 
[42] 
Jeong, H.J.; Ryu, Y.B.; Park, S.J.; Kim, J.H.; Kwon, H.J.; Kim, J.H.; Park, K.H.; Rho, M.C.; Lee, W.S. Neuraminidase inhibitory activities of flavonols isolated from Rhodiola rosea roots and their in vitro anti-influenza viral activities. Bioorg. Med. Chem.,  2009, 17(19), 6816-6823.
[http://dx.doi.org/10.1016/j.bmc.2009.08.036] [PMID:  19729316] 
[43] 
Xue, Y.; Li, H.; Zhang, Y.; Han, X.; Zhang, G.; Li, W.; Zhang, H.; Lin, Y.; Chen, P.; Sun, X.; Liu, Y.; Chu, L.; Zhang, J.; Zhang, M.; Zhang, X. Natural and synthetic flavonoids, novel blockers of the volume-regulated anion channels, inhibit endothelial cell proliferation. Pflugers Arch.,  2018, 470(10), 1473-1483.
[http://dx.doi.org/10.1007/s00424-018-2170-8] [PMID:  29961148] 
[44] 
Nhiem, N.X.; Van Kiem, P.; Van Minh, C.; Hoai, N.T.; Duc, H.V.; Tai, B.H.; Quang, T.H.; Le Anh, H.T.; Yeo, S.G.; Song, J.H.; Cheon, D.S.; Park, M.H.; Ko, H.J.; Kim, S.H. Anti-influenza sesquiterpene from the roots of Reynoutria japonica. Nat. Prod. Commun.,  2014, 9(3), 315-318.
[http://dx.doi.org/10.1177/1934578X1400900308] [PMID:  24689204] 
[45] 
Mani, J.S.; Johnson, J.B.; Steel, J.C.; Broszczak, D.A.; Neilsen, P.M.; Walsh, K.B.; Naiker, M. Natural product-derived phytochemicals as potential agents against coronaviruses: A review. Virus Res.,  2020, 284197989
[http://dx.doi.org/10.1016/j.virusres.2020.197989] [PMID:  32360300] 
[46] 
Ortega, J.T.; Serrano, M.L.; Pujol, F.H.; Rangel, H.R. Role of changes in SARS-CoV-2 spike protein in the interaction with the human ACE2 receptor: An in silico analysis. EXCLI J.,  2020, 19, 410-417.
[PMID:  32210742] 
[47] 
Chan, J.F-W.; Kok, K-H.; Zhu, Z.; Hin, C.; To, K.K-W.; Yuan, S.; Lau, S.K-P.; Woo, P.C-Y.; Yuen, K-Y. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from patients with acute respiratory disease in wuhan, Hubei, China. Emerg. Microbes Infect.,  2020, 9(1), 221-236.
[http://dx.doi.org/10.1080/22221751.2020.1719902] [PMID:  31987001] 
[48] 
Grifoni, A.; Sidney, J.; Zhang, Y.; Scheuermann, R.H.; Peters, B.; Sette, A. A sequence homology and bioinformatic approach can predict candidate targets for immune responses to SARS-CoV-2. Cell Host Microbe,  2020, 27(4), 671-680.e2.
[http://dx.doi.org/10.1016/j.chom.2020.03.002] [PMID:  32183941] 
[49] 
Lu, R.; Zhao, X.; Li, J.; Niu, P.; Yang, B.; Wu, H.; Wang, W.; Song, H.; Huang, B.; Zhu, N.; Bi, Y.; Ma, X.; Zhan, F.; Wang, L.; Hu, T.; Zhou, H.; Hu, Z.; Zhou, W.; Zhao, L.; Chen, J.; Meng, Y.; Wang, J.; Lin, Y.; Yuan, J.; Xie, Z.; Ma, J.; Liu, W.J.; Wang, D.; Xu, W.; Holmes, E.C.; Gao, G.F.; Wu, G.; Chen, W.; Shi, W.; Tan, W. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet,  2020, 395(10224), 565-574.
[http://dx.doi.org/10.1016/S0140-6736(20)30251-8] [PMID:  32007145] 
[50] 
Othman, H.; Bouslama, Z.; Brandenburg, J.T.; da Rocha, J.; Hamdi, Y.; Ghedira, K.; Srairi-Abid, N.; Hazelhurst, S. Interaction of the spike protein RBD from SARS-CoV-2 with ACE2: Similarity with SARS-CoV, hot-spot analysis and effect of the receptor polymorphism. Biochem. Biophys. Res. Commun.,  2020, 527(3), 702-708.
[http://dx.doi.org/10.1016/j.bbrc.2020.05.028] [PMID:  32410735] 
[51] 
Bianchi, M.; Benvenuto, D.; Giovanetti, M.; Angeletti, S.; Ciccozzi, M.; Pascarella, S. Sars-CoV-2 envelope and membrane proteins: structural differences linked to virus characteristics? BioMed Res. Int.,  2020, 20204389089
[http://dx.doi.org/10.1155/2020/4389089] [PMID:  32596311] 
[52] 
Liu, Z.; Xiao, X.; Wei, X.; Li, J.; Yang, J.; Tan, H.; Zhu, J.; Zhang, Q.; Wu, J.; Liu, L. Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential intermediate hosts of SARS-CoV-2. J. Med. Virol.,  2020, 92(6), 595-601.
[http://dx.doi.org/10.1002/jmv.25726] [PMID:  32100877] 
[53] 
Avram, S.; Bologa, C.; Flonta, M.L. Quantitative structure-activity relationship by CoMFA for cyclic urea and nonpeptide-cyclic cyanoguanidine derivatives on wild type and mutant HIV-1 protease. J. Mol. Model.,  2005, 11(2), 105-115.
[http://dx.doi.org/10.1007/s00894-004-0226-5] [PMID:  15714296] 
[54] 
Buiu, C.; Putz, M.V.; Avram, S. Learning the relationship between the primary structure of HIV envelope glycoproteins and neutralization activity of particular antibodies by using artificial neural networks. Int. J. Mol. Sci.,  2016, 17(10), 1710.
[http://dx.doi.org/10.3390/ijms17101710] [PMID:  27727189] 
[55] 
Avram, S.; Milac, A-L.; Borcan, L-C.; Mihailescu, D.; Borcan, F.; Castanho, M. Designing of artificial peptides for an improved antiviral activity. Curr. Proteomics,  2018, 15(4), 258-266.
[http://dx.doi.org/10.2174/1570164615666180409151111] 
[56] 
Kim, S.; Chen, J.; Cheng, T.; Gindulyte, A.; He, J.; He, S.; Li, Q.; Shoemaker, B.A.; Thiessen, P.A.; Yu, B.; Zaslavsky, L.; Zhang, J.; Bolton, E.E. PubChem 2019 update: Improved access to chemical data. Nucleic Acids Res.,  2019, 47(D1), D1102-D1109.
[http://dx.doi.org/10.1093/nar/gky1033] [PMID:  30371825] 
[57] 
MOE (Molecular Operating Environment) available from Chemical Computing Group Inc. Available from: https://www.chemcomp.com/
[58] 
Ahmad, N.; Farman, A.; Badshah, S.L.; Ur Rahman, A.; Ur Rashid, H.; Khan, K. Molecular modeling, simulation and docking study of ebola virus glycoprotein. J. Mol. Graph. Model.,  2017, 72, 266-271.
[http://dx.doi.org/10.1016/j.jmgm.2016.12.010] [PMID:  28160722] 
[59] 
Wahl, J.; Freyss, J.; von Korff, M.; Sander, T. Accuracy evaluation and addition of improved dihedral parameters for the MMFF94s. J. Cheminform.,  2019, 11(1), 53.
[http://dx.doi.org/10.1186/s13321-019-0371-6] [PMID:  31392432] 
[60] 
Saotome, K.; Murthy, S.E.; Kefauver, J.M.; Whitwam, T.; Patapoutian, A.; Ward, A.B. Structure of the mechanically activated ion channel Piezo1. Nature,  2018, 554(7693), 481-486.
[http://dx.doi.org/10.1038/nature25453] [PMID:  29261642] 
[61] 
Vlaicu, I.D.; Olar, R.; Maxim, C.; Chifiriuc, M.C.; Bleotu, C.; Stănică, N.; Vasile Scăeţeanu, G.; Dulea, C.; Avram, S.; Badea, M. Evaluating the biological potential of some new cobalt (II) complexes with acrylate and benzimidazole derivatives. Appl. Organomet. Chem.,  2019, 33(7)e4976
[http://dx.doi.org/10.1002/aoc.4976] 
[62] 
Cruciani, G.; Crivori, P.; Carrupt, P.A.; Testa, B. Molecular fields in quantitative structure–permeation relationships: The VolSurf approach. J. Mol. Struct. THEOCHEM,  2000, 503, 17-30.
[http://dx.doi.org/10.1016/S0166-1280(99)00360-7] 
[63] 
Labute, P. MOE LogP (Octanol/Water) Model unpublished. Source code in $MOE/lib/svl/quasar.svl/q_logp.svl,  1998.
[64] 
Oprea, T.I. Property distribution of drug-related chemical databases. J. Comput. Aided Mol. Des.,  2000, 14(3), 251-264.
[http://dx.doi.org/10.1023/A:1008130001697] [PMID:  10756480] 
[65] 
Hall, L.H.; Kier, L.B. The molecular connectivity chi indexes and kappa shape indexes in structure-property modeling. Rev. Comput. Chem.,  1991, 367-422.
[http://dx.doi.org/10.1002/9780470125793.ch9] 
[66] 
Gasteiger, J.; Marsili, M. Iterative partial equalization of orbital electronegativity-a rapid access to atomic charges. Tetrahedron,  1980, 36, 3219-3228.
[http://dx.doi.org/10.1016/0040-4020(80)80168-2] 
[67] 
O’Boyle, N.M.; Sayle, R.A. Comparing structural fingerprints using a literature-based similarity benchmark. J. Cheminform.,  2016, 8, 36.
[http://dx.doi.org/10.1186/s13321-016-0148-0] [PMID:  27382417] 
[68] 
Muegge, I.; Mukherjee, P. An overview of molecular fingerprint similarity search in virtual screening. Expert Opin. Drug Discov.,  2016, 11(2), 137-148.
[http://dx.doi.org/10.1517/17460441.2016.1117070] [PMID:  26558489] 
[69] 
Molinspiration Calculation of Molecular Properties and Bioactivity Score. Available from: https://www.molinspiration.com/cgi-bin/properties
[70] 
Gasteiger, E.; Gattiker, A.; Hoogland, C.; Ivanyi, I.; Appel, R.D.; Bairoch, A. ExPASy: The proteomics server for in-depth protein knowledge and analysis. Nucleic Acids Res.,  2003, 31(13), 3784-3788.
[http://dx.doi.org/10.1093/nar/gkg563] [PMID:  12824418] 
[71] 
Liu, X.; Vogt, I.; Haque, T.; Campillos, M. HitPick: A web server for hit identification and target prediction of chemical screenings. Bioinformatics,  2013, 29(15), 1910-1912.
[http://dx.doi.org/10.1093/bioinformatics/btt303] [PMID:  23716196] 
[72] 
Nickel, J.; Gohlke, B. O.; Erehman, J.; Banerjee, P.; Rong, W. W.; Goede, A.; Dunkel, M.; Preissner, R. SuperPred: Update on Drug Classification and Target Prediction. Nucleic Acids Res., 2014, 42(Web Server issue), W26-W31.
[73] 
Salata, C.; Calistri, A.; Parolin, C.; Baritussio, A.; Palù, G. Antiviral activity of cationic amphiphilic drugs. Expert Rev. Anti Infect. Ther.,  2017, 15(5), 483-492.
[http://dx.doi.org/10.1080/14787210.2017.1305888] [PMID:  28286997] 
[74] 
Rahaman, J.; Siltberg-Liberles, J. Avoiding regions symptomatic of conformational and functional flexibility to identify antiviral targets in current and future coronaviruses. Genome Biol. Evol.,  2016, 8(11), 3471-3484.
[http://dx.doi.org/10.1093/gbe/evw246] [PMID:  27797946] 
[75] 
Berry, M.; Fielding, B.C.; Gamieldien, J. Potential broad spectrum inhibitors of the coronavirus 3CLpro: A virtual screening and structure-based drug design study. Viruses,  2015, 7(12), 6642-6660.
[http://dx.doi.org/10.3390/v7122963] [PMID:  26694449] 
[76] 
Morse, J.S.; Lalonde, T.; Xu, S.; Liu, W.R. Learning from the past: possible urgent prevention and treatment options for severe acute respiratory infections caused by 2019-nCoV. ChemBioChem,  2020, 21(5), 730-738.
[http://dx.doi.org/10.1002/cbic.202000047] [PMID:  32022370] 
[77] 
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(5), 369-381.
[http://dx.doi.org/10.1007/s13238-014-0026-3] [PMID:  24622840] 
[78] 
Su, H.X.; Yao, S.; Zhao, W.F.; Li, M.J.; Liu, J.; Shang, W.J.; Xie, H.; Ke, C.Q.; Hu, H.C.; Gao, M.N.; Yu, K.Q.; Liu, H.; Shen, J.S.; Tang, W.; Zhang, L.K.; Xiao, G.F.; Ni, L.; Wang, D.W.; Zuo, J.P.; Jiang, H.L.; Bai, F.; Wu, Y.; Ye, Y.; Xu, Y.C. Anti-SARS-CoV-2 activities in vitro of Shuanghuanglian preparations and bioactive ingredients. Acta Pharmacol. Sin.,  2020, 41(9), 1167-1177.
[http://dx.doi.org/10.1038/s41401-020-0483-6] [PMID:  32737471] 
[79] 
Bolcato, G.; Bissaro, M.; Pavan, M.; Sturlese, M.; Moro, S. Targeting the coronavirus SARS-CoV-2: Computational insights into the mechanism of action of the protease inhibitors lopinavir, ritonavir and nelfinavir. Sci. Rep.,  2020, 10(1), 20927.
[http://dx.doi.org/10.1038/s41598-020-77700-z] [PMID:  33262359] 
[80] 
Jin, Z.; Du, X.; Xu, Y.; Deng, Y.; Liu, M.; Zhao, Y.; Zhang, B.; Li, X.; Zhang, L.; Peng, C.; Duan, Y.; Yu, J.; Wang, L.; Yang, K.; Liu, F.; Jiang, R.; Yang, X.; You, T.; Liu, X.; Yang, X.; Bai, F.; Liu, H.; Liu, X.; Guddat, L.W.; Xu, W.; Xiao, G.; Qin, C.; Shi, Z.; Jiang, H.; Rao, Z.; Yang, H. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature,  2020, 582(7811), 289-293.
[http://dx.doi.org/10.1038/s41586-020-2223-y] [PMID:  32272481] 
[81] 
Yin, W.; Mao, C.; Luan, X.; Shen, D-D.; Shen, Q.; Su, H.; Wang, X.; Zhou, F.; Zhao, W.; Gao, M.; Chang, S.; Xie, Y.C.; Tian, G.; Jiang, H.W.; Tao, S.C.; Shen, J.; Jiang, Y.; Jiang, H.; Xu, Y.; Zhang, S.; Zhang, Y.; Xu, H.E. Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir. Science,  2020, 368(6498), 1499-1504.
[http://dx.doi.org/10.1126/science.abc1560] [PMID:  32358203] 
[82] 
Laskowski, R.A.; Swindells, M.B. LigPlot+: Multiple ligand-protein interaction diagrams for drug discovery. J. Chem. Inf. Model.,  2011, 51(10), 2778-2786.
[http://dx.doi.org/10.1021/ci200227u] [PMID:  21919503] 
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DOI https://dx.doi.org/10.2174/1573406417666210806154129	Print ISSN 1573-4064
Publisher Name Bentham Science Publisher	Online ISSN 1875-6638
Medicinal Chemistry

Structural Bioinformatics Used to Predict the Protein Targets of Remdesivir and Flavones in SARS-CoV-2 Infection

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