In silico identification of SARS-CoV-2 cell entry inhibitors from selected natural antivirals
Yusuf Şimşek, Sahra Setenay Baran, Belma Aslım
Journal of Molecular Graphics and Modelling, doi:10.1016/j.jmgm.2021.108038
The aim of this study is to identify potential drug-like molecules against SARS-CoV-2 virus among the natural antiviral compounds published in the Encyclopedia of Traditional Chinese Medicine. To test inhibition capability of these compounds first, we docked them with Spike protein, angiotensin-converting enzyme 2 (ACE2) (PDB ID: 6M0J) and neuropilin 1 (NRP1) (PDB ID: 7JJC) receptors, and found significant docking scores with extra precision up to -11 kcal/mol. Then, their stability in the binding pockets were further evaluated with molecular dynamics simulation. Eight natural antiviral compounds were identified as potential inhibitors against SARS-CoV-2 cell entry after 200 ns molecular dynamics simulations. We found CMP-3, CMP-4, CMP-5, CMP-6 and CMP-8 are strong binders for the spike protein, CMP-1, CMP-2, CMP-4, CMP-5 and CMP-7 are strong binders for the neuropilin receptor, and CMP-5 is a strong binder for the ACE2. Quercetin derivatives (CMP-4, CMP-5, CMP-6 and CMP-7) were found highly stable in the active domain of NRP1, ACE2 and Spike protein. Especially, CMP-5 showed an inhibitory activity for all targets. These natural antivirals may be potential drug candidates for the prevention of SARS-CoV-2 infection.
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.jmgm.2021.108038.
References
Abian, Ortega-Alarcon, Jimenez-Alesanco, Ceballos-Laita, Vega et al., Structural stability of SARS-CoV-2 3clpro and identification of quercetin as an inhibitor by experimental screening, Int. J. Biol. Macromol,
doi:10.1016/j.ijbiomac.2020.07.235Al-Tawfiq, Momattin, Dib, Memish, Ribavirin and interferon therapy in patients infected with the middle east respiratory syndrome coronavirus: an observational study, Int. J. Infect. Dis,
doi:10.1016/j.ijid.2013.12.003Aucoin, Cooley, Saunders, Cardozo, Remy et al., The effect of quercetin on the prevention or treatment of COVID-19 and other respiratory tract infections in humans: a rapid review, Advances in Integrative Medicine,
doi:10.1016/j.aimed.2020.07.007Beigel, Tomashek, Dodd, Mehta, Zingman et al., Remdesivir for the treatment of covid-19 -final report, N. Engl. J. Med,
doi:10.1056/NEJMoa2007764Berendsen, Grigera, Straatsma, The missing term in effective pair potentials, J. Phys. Chem,
doi:10.1021/j100308a038Berendsen, Postma, Van Gunsteren, Dinola, Haak, Molecular dynamics with coupling to an external bath, J. Chem. Phys,
doi:10.1063/1.448118Bessière, Roccia, Delinière, Charrière, Chevalier et al., Assessment of QT intervals in a case series of patients with coronavirus disease 2019 (COVID-19) infection treated with hydroxychloroquine alone or in combination with azithromycin in an intensive care unit, JAMA Cardiology,
doi:10.1001/jamacardio.2020.1787Bhatnagar, Murhekar, Soneja, Gupta, Giri et al., Lopinavir/ritonavir combination therapy amongst symptomatic coronavirus disease 2019 patients in India: protocol for restricted public health emergency use, Indian J. Med. Res,
doi:10.4103/ijmr.IJMR_502_20Booth, Matukas, Tomlinson, Rachlis, Rose et al., Clinical features and short-term outcomes of 144 patients with SARS in the greater toronto area, JAMA,
doi:10.1001/jama.289.21.JOC30885Borba, Val, Sampaio, Alexandre, Melo et al., Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, JAMA Network Open,
doi:10.1001/jamanetworkopen.2020.8857Bowers, Chow, Xu, Dror, Eastwood et al., Scalable algorithms for molecular dynamics simulations on commodity clusters,
doi:10.1109/sc.2006.54Brown, Won, Graham, Dinnon, Sims et al., Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent rna dependent rna polymerase, Antivir. Res,
doi:10.1016/j.antiviral.2019.104541Cai, Yang, Liu, Chen, Shu et al., Experimental treatment with favipiravir for covid-19: an open-label control study, Engineering,
doi:10.1016/j.eng.2020.03.007Cantuti-Castelvetri, Ojha, Pedro, Djannatian, Franz et al., Neuropilin-1 facilitates sars-cov-2 cell entry and infectivity, Science,
doi:10.1126/science.abd2985Cao, Wang, Wen, Liu, Wang et al., A trial of lopinavir-ritonavir in adults hospitalized with severe covid-19, N. Engl. J. Med,
doi:10.1056/NEJMoa2001282Chen, Liu, Liu, Liu, Xu et al., A pilot study of hydroxychloroquine in treatment of patients with moderate covid-19, Zhejiang da xue xue bao, Yi xue ban = Journal of Zhejiang University. Medical sciences
Chen, Oezguen, Urvil, Ferguson, Dann et al., Regulation of protein-ligand binding affinity by hydrogen bond pairing, Science Advances,
doi:10.1126/sciadv.1501240Chikhale, Gurav, Patil, Sinha, Prasad et al., Sars-cov-2 host entry and replication inhibitors from indian ginseng: an in-silico approach, 0 (0), J. Biomol. Struct. Dyn,
doi:10.1080/07391102.2020.1778539Chong, Song, Seo, Choi, Shin, Antiviral treatment guidelines for middle east respiratory syndrome, Infection & Chemotherapy,
doi:10.3947/ic.2015.47.3.212Choudhary, Malik, Tomar, Identification of sars-cov-2 cell entry inhibitors by drug repurposing using in silico structure-based virtual screening approach, Front. Immunol,
doi:10.3389/fimmu.2020.01664Chu, Cheng, Hung, Wong, Chan et al., Role of lopinavir/ritonavir in the treatment of sars: initial virological and clinical findings, Thorax,
doi:10.1136/thorax.2003.012658Daly, Simonetti, Klein, Chen, Williamson et al., Neuropilin-1 is a host factor for sars-cov-2 infection, Science,
doi:10.1126/science.abd3072Di Pierro, Khan, Bertuccioli, Maffioli, Derosa et al., Quercetin phytosome® as a potential drug for covid-19, Minerva Gastroenterol. Dietol,
doi:10.23736/S1121-421X.20.02771-3Doi, Ikeda, Hayase, Moriya, Morimura et al., the COVID-UTH Study Group, Nafamostat mesylate treatment in combination with favipiravir for patients critically ill with covid-19: a case series, Crit. Care,
doi:10.1186/s13054-020-03078-zFanunza, Iampietro, Distinto, Corona, Quartu et al., Quercetin blocks ebola virus infection by counteracting the VP24 interferon-inhibitory function, Antimicrob. Agents Chemother,
doi:10.1128/aac.00530-20Friesner, Banks, Murphy, Halgren, Klicic et al., Glide: a new approach for rapid, accurate docking and scoring. 1. method and assessment of docking accuracy, J. Med. Chem,
doi:10.1021/jm0306430Friesner, Murphy, Repasky, Frye, Greenwood et al., Extra precision glide:docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes, J. Med. Chem,
doi:10.1021/jm051256oGautret, Lagier, Parola, Hoang, Meddeb et al., Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label nonrandomized clinical trial, Int. J. Antimicrob. Agents,
doi:10.1016/j.ijantimicag.2020.105949Greenwood, Calkins, Sullivan, Shelley, Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution, J. Comput. Aided Mol. Des,
doi:10.1007/s10822-010-9349-1Halgren, Murphy, Friesner, Beard, Frye et al., Glide: a new approach for rapid, accurate docking and scoring. 2. enrichment factors in database screening, J. Med. Chem,
doi:10.1021/jm030644sHall, Ji, A search for medications to treat covid-19 via in silico molecular docking models of the sars-cov-2 spike glycoprotein and 3cl protease, Trav. Med. Infect. Dis,
doi:10.1016/j.tmaid.2020.101646Harder, Damm, Maple, Wu, Reboul et al., OPLS3: a force field providing broad coverage of drug-like small molecules and proteins, J. Chem. Theor. Comput,
doi:10.1021/acs.jctc.5b00864Holshue, Debolt, Lindquist, Lofy, Wiesman et al., First case of 2019 novel coronavirus in the United States, N. Engl. J. Med,
doi:10.1056/NEJMoa2001191Horby, Mafham, Bell, Linsell, Staplin et al., Lopinavir-ritonavir in patients admitted to hospital with covid-19 (recovery): a randomised, controlled, open-label, platform trial, Lancet,
doi:10.1016/S0140-6736(20)32013-4Huang, Li, Leung, Liu, Liu et al., A review of therapeutic agents and Chinese herbal medicines against SARS-COV-2 (COVID-19), Pharmacol. Res,
doi:10.1016/j.phrs.2020.104929Huang, Pearce, Zhang, De novo design of protein peptides to block association of the sars-cov-2 spike protein with human ace2, Aging
Jacobson, Friesner, Xiang, Honig, On the role of the crystal environment in determining protein side-chain conformations, J. Mol. Biol,
doi:10.1016/s0022-2836(02)00470-9Jacobson, Pincus, Rapp, Day, Honig et al., A hierarchical approach to all-atom protein loop prediction, Proteins: Structure, Function, and Bioinformatics,
doi:10.1002/prot.10613Jo, Kim, Kim, Shin, Kim, Characteristics of flavonoids as potent MERS-CoV 3c-like protease inhibitors, Chem. Biol. Drug Des,
doi:10.1111/cbdd.13604Jomah, Asdaq, Al-Yamani, Clinical efficacy of antivirals against novel coronavirus (covid-19): a review, J. Infect.Public Health,
doi:10.1016/j.jiph.2020.07.013Khalili, Zhu, Mak, Yan, Zhu, Novel coronavirus treatment with ribavirin: groundwork for an evaluation concerning covid-19, J. Med. Virol,
doi:10.1002/jmv.25798Koren, King, Knowles, Phillips, Ribavirin in the treatment of sars: a new trick for an old drug? CMAJ, Can. Med. Assoc. J.) : Canadian Medical Association journal = journal de l'Association medicale canadienne
Krafcikova, Silhan, Nencka, Boura, Structural analysis of the sars-cov-2 methyltransferase complex involved in rna cap creation bound to sinefungin, Nat. Commun,
doi:10.1038/s41467-020-17495-9Lan, Ge, Yu, Shan, Zhou et al., Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor, Nature,
doi:10.1038/s41586-020-2180-5Li, Xie, Lin, Cai, Wen et al., Efficacy and safety of lopinavir/ritonavir or arbidol in adult patients with mild/ moderate covid-19: an exploratory randomized controlled trial, Med,
doi:10.1016/j.medj.2020.04.001Luan, Lu, Jin, Zhang, Spike protein recognition of mammalian ace2 predicts the host range and an optimized ace2 for sars-cov-2 infection, Biochem. Biophys. Res. Commun,
doi:10.1016/j.bbrc.2020.03.047Mahévas, Tran, Roumier, Chabrol, Paule et al., Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data, BMJ,
doi:10.1136/bmj.m1844Martinot, Jary, Fafi-Kremer, Leducq, Delagreverie et al., Remdesivir failure with SARS-CoV-2 RNA-dependent RNA-polymerase mutation in a B-cell immunodeficient patient with protracted Covid-19, Clin. Infect. Dis,
doi:10.1093/cid/ciaa1474Mehrbod, Hudy, Shyntum, Markowski, Łos et al., Quercetin as a natural therapeutic candidate for the treatment of influenza virus, Biomolecules,
doi:10.3390/biom11010010Morgenstern, Michaelis, Baer, Doerr, Cinatl, Ribavirin and interferon-beta synergistically inhibit sars-associated coronavirus replication in animal and human cell lines, Biochem. Biophys. Res. Commun,
doi:10.1016/j.bbrc.2004.11.128Morra, Van Thanh, Kamel, Ghazy, Altibi et al., Clinical outcomes of current medical approaches for middle east respiratory syndrome: a systematic review and meta-analysis, Rev. Med. Virol,
doi:10.1002/rmv.1977Mu, Sheng, Wang, Amin, Li et al., Potential compound from herbal food of rhizoma polygonati for treatment of covid-19 analyzed by network pharmacology: viral and cancer signaling mechanisms, J.Funct. Foods,
doi:10.1016/j.jff.2020.104149Mu, Sheng, Wang, Amin, Li et al., Potential compound from herbal food of rhizoma polygonati for treatment of covid-19 analyzed by network pharmacology: viral and cancer signaling mechanisms, Journal of Functional Foods,
doi:10.1016/j.jff.2020.104149Nguyen, Woo, Kang, Nguyen, Kim et al., Flavonoid-mediated inhibition of SARS coronavirus 3c-like protease expressed in pichia pastoris, Biotechnol. Lett,
doi:10.1007/s10529-011-0845-8Nutho, Mahalapbutr, Hengphasatporn, Pattaranggoon, Simanon et al., Why are lopinavir and ritonavir effective against the newly emerged coronavirus 2019? atomistic insights into the inhibitory mechanisms, Biochemistry,
doi:10.1021/acs.biochem.0c00160Pasquau, Hidalgo-Tenorio, Montes, Romero-Palacios, Vergas et al., On behalf of the QoLKAMON STUDY GROUP, High quality of life, treatment tolerability, safety and efficacy in hiv patients switching from triple therapy to lopinavir/ ritonavir monotherapy: a randomized clinical trial, PloS One,
doi:10.1371/journal.pone.0195068Pruijssers, George, Schäfer, Leist, Gralinksi et al., Remdesivir inhibits sars-cov-2 in human lung cells and chimeric sars-cov expressing the sars-cov-2 rna polymerase in mice, Cell Rep,
doi:10.1016/j.celrep.2020.107940Rameshkumar, Indu, Arunagirinathan, Venkatadri, El-Serehy et al., Computational selection of flavonoid compounds as inhibitors against sars-cov-2 main protease, rna-dependent rna polymerase and spike proteins: a molecular docking study, Saudi J. Biol. Sci
Riva, Ronchi, Petrangolini, Bosisio, Allegrini, Improved oral absorption of quercetin from quercetin phytosome®, a new delivery system based on food grade lecithin, Eur. J. Drug Metab. Pharmacokinet,
doi:10.1007/s13318-018-0517-3Ryu, Jeong, Kim, Kim, Park et al., Biflavonoids from torreya nucifera displaying SARS-CoV 3clpro inhibition, Bioorg. Med. Chem,
doi:10.1016/j.bmc.2010.09.035Sachdeva, Wadhwa, Kumari, Hussain, Jha et al., In silico potential of approved antimalarial drugs for repurposing against covid-19, OMICS,
doi:10.1089/omi.2020.0071Saleh, Gabriels, Chang, Kim, Mansoor et al., Effect of chloroquine, hydroxychloroquine, and azithromycin on the corrected qt interval in patients with sars-cov-2 infection, Circulation: Arrhythmia and Electrophysiology,
doi:10.1161/CIRCEP.120.008662Sanders, Monogue, Jodlowski, Cutrell, Pharmacologic treatments for coronavirus disease 2019 (COVID-19),
doi:10.1001/jama.2020.6019Sastry, Adzhigirey, Day, Annabhimoju, Sherman, Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments, J. Comput. Aided Mol. Des,
doi:10.1007/s10822-013-9644-8Schrezenmeier, Dörner, Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology, Nat. Rev. Rheumatol,
doi:10.1038/s41584-020-0372-xShan, Klepeis, Eastwood, Dror, Shaw, Gaussian split ewald: a fast ewald mesh method for molecular simulation, J. Chem. Phys,
doi:10.1063/1.1839571Sheahan, Sims, Graham, Menachery, Gralinski et al., Broad-spectrum antiviral gs-5734 inhibits both epidemic and zoonotic coronaviruses, Sci. Transl. Med,
doi:10.1126/scitranslmed.aal3653Shelley, Cholleti, Frye, Greenwood, Timlin et al., Epik: a software program for pK a prediction and protonation state generation for drug-like molecules, J. Comput. Aided Mol. Des,
doi:10.1007/s10822-007-9133-zSinha, Prasad, Islam, Gurav, Patil et al., Identification of bioactive compounds from glycyrrhiza glabra as possible inhibitor of sars-cov-2 spike glycoprotein and non-structural protein-15: a pharmacoinformatics study, 0 (0), J. Biomol. Struct. Dyn,
doi:10.1080/07391102.2020.1779132Sinha, Shakya, Prasad, Singh, Gurav et al., An in-silico evaluation of different saikosaponins for their potency against sarscov-2 using nsp15 and fusion spike glycoprotein as targets, J. Biomol. Struct. Dyn,
doi:10.1080/07391102.2020.1762741Smith, Smith, Repurposing Therapeutics for Covid-19: Supercomputer-Based Docking to the Sars-Cov-2 Viral Spike Protein and Viral Spike, Protein-Human Ace,
doi:10.26434/chemrxiv.11871402.v3Takahashi, Iwasaki, Watanabe, Ichinose, Okada et al., Case studies of SARS-CoV-2 treated with favipiravir among patients in critical or severe condition, Int. J. Infect. Dis,
doi:10.1016/j.ijid.2020.08.047Takemura, Kitao, Water model tuning for improved reproduction of rotational diffusion and NMR spectral density, J. Phys. Chem. B,
doi:10.1021/jp301100gUnni, Aouti, Thiyagarajan, Padmanabhan, Identification of a repurposed drug as an inhibitor of spike protein of human coronavirus sars-cov-2 by computational methods, J. Biosci
Vargas, Servillo, Einav, Lopinavir/ritonavir for the treatment of sars, mers and covid-19: a systematic review, Eur. Rev. Med. Pharmacol. Sci,
doi:10.26355/eurrev_202008_22659Walls, Park, Tortorici, Wall, Mcguire et al., Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein, Cell,
doi:10.1016/j.cell.2020.02.058Wang, Li, Jiang, Xi, Zhu, Assessment of the efficacy and safety of ribavirin in treatment of coronavirus-related pneumonia (SARS, MERS and COVID-19), Medicine,
doi:10.1097/md.0000000000022379Wang, Li, Li, Zhang, Wang et al., The genetic sequence, origin, and diagnosis of SARS-CoV-2, Eur. J. Clin. Microbiol. Infect. Dis,
doi:10.1007/s10096-020-03899-4Wang, Zhang, Du, Du, Zhao et al., Remdesivir in adults with severe covid-19: a randomised, double-blind, placebo-controlled, multicentre trial, Lancet,
doi:10.1016/S0140-6736(20)31022-9Williamson, Kerimi, Testing of natural products in clinical trials targeting the SARS-CoV-2 (covid-19) viral spike protein-angiotensin converting enzyme-2 (ACE2) interaction, Biochem. Pharmacol,
doi:10.1016/j.bcp.2020.114123Wu, Li, Li, He, Jiang et al., Quercetin as an antiviral agent inhibits influenza a virus (IAV) entry, Viruses,
doi:10.3390/v8010006Xia, Zhu, Liu, Lan, Xu et al., Fusion mechanism of 2019-ncov and fusion inhibitors targeting hr1 domain in spike protein, Cell. Mol. Immunol,
doi:10.1038/s41423-020-0374-2Yang, Islam, Wang, Li, Chen, Traditional Chinese medicine in the treatment of patients infected with 2019-new coronavirus (sars-cov-2): a review and perspective, Int. J. Biol. Sci
Yao, Qian, Zhu, Wang, Wang, A systematic review of lopinavir therapy for sars coronavirus and mers coronavirus-a possible reference for coronavirus disease-19 treatment option, J. Med. Virol,
doi:10.1002/jmv.25729Yao, Qian, Zhu, Wang, Wang, A systematic review of lopinavir therapy for sars coronavirus and mers coronavirus-a possible reference for coronavirus disease-19 treatment option, J. Med. Virol,
doi:10.1002/jmv.25729Ye, Luo, Ye, She, Sun et al., Network pharmacology, molecular docking integrated surface plasmon resonance technology reveals the mechanism of toujie quwen granules against coronavirus disease 2019 pneumonia, Phytomedicine,
doi:10.1016/j.phymed.2020.153401Yin, Mao, Luan, Shen, Shen et al., Structural basis for inhibition of the rna-dependent rna polymerase from sars-cov-2 by remdesivir, Science,
doi:10.1126/science.abc1560Yu, Li, Chen, Zhou, Wang et al., Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19, Sci. China Life Sci,
doi:10.1007/s11427-020-1732-2Yu, Zhu, Xu, Yao, Zhang et al., Glycyrrhizic acid exerts inhibitory activity against the spike protein of sars-cov-2, Phytomedicine,
doi:10.1016/j.phymed.2020.153364Zhang, Wu, Zhang, Deng, Peng, In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus, J. Integr. Med,
doi:10.1016/j.joim.2020.02.005Zhou, Xie, Yan, Encyclopedia of Traditional Chinese Medicines -Molecular Structures, Pharmacological Activities, Natural Sources and Applications,
doi:10.1007/978-3-642-16744-7
