Utilizing natural compounds as ligands to disrupt the binding of SARS-CoV-2 receptor-binding domain to angiotensin-converting enzyme 2, impeding viral infection
et al., Phytochemistry Letters, doi:10.1016/j.phytol.2025.102999, Jun 2025
Curcumin for COVID-19
16th treatment shown to reduce risk in
February 2021, now with p = 0.0000000061 from 28 studies.
No treatment is 100% effective. Protocols
combine treatments.
6,300+ studies for
210+ treatments. c19early.org
|
In silico study showing that curcumin and arachidonic acid bind strongly to the SARS-CoV-2 receptor-binding domain (RBD), ACE2 receptor, and their complex interface, potentially disrupting viral infection. Curcumin demonstrated the highest binding affinity for the RBD site and RBD-ACE2 complex. Molecular dynamics simulations over 100 ns confirmed the stability of the curcumin-ACE2-RBD complex with RMSD values of 1-1.5 Å.
59 preclinical studies support the efficacy of curcumin for COVID-19:
In silico studies predict inhibition of SARS-CoV-2 with curcumin or metabolites via binding to the spikeA,4,5,10,15,17,23,26 (and specifically the receptor binding domainB,1,3,13,16,19 ), MproC,3-5,10,12,14-16,18,19,21,24,26,27,29,46 , RNA-dependent RNA polymeraseD,3-5,16,25 , PLproE,5, ACE2F,1,17,18,20 , nucleocapsidG,11,28 , nsp10H,28, and helicaseI,34 proteins, and inhibition of spike-ACE2 interactionJ,2.
In vitro studies demonstrate inhibition of the spikeA,39 (and specifically the receptor binding domainB,49), MproC,22,39,46,48 , ACE2F,49, and TMPRSS2K,49 proteins, and inhibition of spike-ACE2 interactionJ,2,32 .
In vitro studies demonstrate efficacy in Calu-3L,47, A549M,39, 293TN,6, HEK293-hACE2O,22,37 , 293T/hACE2/TMPRSS2P,38, Vero E6Q,12,16,26,37,39,41,43,45,47 , and SH-SY5YR,36 cells.
Curcumin decreases pro-inflammatory cytokines induced by SARS-CoV-2 in peripheral blood mononuclear cells45, alleviates SARS-CoV-2 spike protein-induced mitochondrial membrane damage and oxidative stress6, may limit COVID-19 induced cardiac damage by inhibiting the NF-κB signaling pathway which mediates the profibrotic effects of the SARS-CoV-2 spike protein on cardiac fibroblasts33, is predicted to inhibit the interaction between the SARS-CoV-2 spike protein receptor binding domain and the human ACE2 receptor for the delta and omicron variants13, lowers ACE2 and STAT3, curbing lung inflammation and ARDS in preclinical COVID-19 models30, inhibits SARS-CoV-2 ORF3a ion channel activity, which contributes to viral pathogenicity and cytotoxicity40, has direct virucidal action by disrupting viral envelope integrity42, and can function as a photosensitizer in photodynamic therapy to generate reactive oxygen species that damage the virus42.
1.
Wu et al., Utilizing natural compounds as ligands to disrupt the binding of SARS-CoV-2 receptor-binding domain to angiotensin-converting enzyme 2, impeding viral infection, Phytochemistry Letters, doi:10.1016/j.phytol.2025.102999.
2.
Najimi et al., Phytochemical Inhibitors of SARS‐CoV‐2 Entry: Targeting the ACE2‐RBD Interaction with l‐Tartaric Acid, l‐Ascorbic Acid, and Curcuma longa Extract, ChemistrySelect, doi:10.1002/slct.202406035.
3.
Rajamanickam et al., Exploring the Potential of Siddha Formulation MilagaiKudineer-Derived Phytotherapeutics Against SARS-CoV-2: An In-Silico Investigation for Antiviral Intervention, Journal of Pharmacy and Pharmacology Research, doi:10.26502/fjppr.0105.
4.
Al balawi et al., Assessing multi-target antiviral and antioxidant activities of natural compounds against SARS-CoV-2: an integrated in vitro and in silico study, Bioresources and Bioprocessing, doi:10.1186/s40643-024-00822-z.
5.
Haque et al., Exploring potential therapeutic candidates against COVID-19: a molecular docking study, Discover Molecules, doi:10.1007/s44345-024-00005-5.
6.
Zhang et al., Computational Discovery of Mitochondrial Dysfunction Biomarkers in Severe SARS-CoV-2 Infection: Facilitating Pytomedicine Screening, Phytomedicine, doi:10.1016/j.phymed.2024.155784.
7.
Öztürkkan et al., In Silico investigation of the effects of curcuminoids on the spike protein of the omicron variant of SARS-CoV-2, Baku State University Journal of Chemistry and Material Sciences, 1:2, bsuj.bsu.edu.az/uploads/pdf/ec4204d62f7802de54e6092bf7860029.pdf.
8.
Yunze et al., Therapeutic effect and potential mechanism of curcumin, an active ingredient in Tongnao Decoction, on COVID-19 combined with stroke: a network pharmacology study and GEO database mining, Research Square, doi:10.21203/rs.3.rs-4329762/v1.
9.
Agamah et al., Network-based multi-omics-disease-drug associations reveal drug repurposing candidates for COVID-19 disease phases, ScienceOpen, doi:10.58647/DRUGARXIV.PR000010.v1.
10.
Boseila et al., Throat spray formulated with virucidal Pharmaceutical excipients as an effective early prophylactic or treatment strategy against pharyngitis post-exposure to SARS CoV-2, European Journal of Pharmaceutics and Biopharmaceutics, doi:10.1016/j.ejpb.2024.114279.
11.
Hidayah et al., Bioinformatics study of curcumin, demethoxycurcumin, bisdemethoxycurcumin and cyclocurcumin compounds in Curcuma longa as an antiviral agent via nucleocapsid on SARS-CoV-2 inhibition, International Conference on Organic and Applied Chemistry, doi:10.1063/5.0197724.
12.
Singh et al., Unlocking the potential of phytochemicals in inhibiting SARS-CoV-2 M Pro protein - An in-silico and cell-based approach, Research Square, doi:10.21203/rs.3.rs-3888947/v1.
13.
Kant et al., Structure-based drug discovery to identify SARS-CoV2 spike protein–ACE2 interaction inhibitors, Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2023.2300060.
14.
Naderi Beni et al., In silico studies of anti-oxidative and hot temperament-based phytochemicals as natural inhibitors of SARS-CoV-2 Mpro, PLOS ONE, doi:10.1371/journal.pone.0295014.
15.
Moschovou et al., Exploring the Binding Effects of Natural Products and Antihypertensive Drugs on SARS-CoV-2: An In Silico Investigation of Main Protease and Spike Protein, International Journal of Molecular Sciences, doi:10.3390/ijms242115894.
16.
Eleraky et al., Curcumin Transferosome-Loaded Thermosensitive Intranasal in situ Gel as Prospective Antiviral Therapy for SARS-Cov-2, International Journal of Nanomedicine, doi:10.2147/IJN.S423251.
17.
Singh (B) et al., Computational studies to analyze effect of curcumin inhibition on coronavirus D614G mutated spike protein, The Seybold Report, doi:10.17605/OSF.IO/TKEXJ.
18.
Thapa et al., In-silico Approach for Predicting the Inhibitory Effect of Home Remedies on Severe Acute Respiratory Syndrome Coronavirus-2, Makara Journal of Science, doi:10.7454/mss.v27i3.1609.
19.
Srivastava et al., Paradigm of Well-Orchestrated Pharmacokinetic Properties of Curcuminoids Relative to Conventional Drugs for the Inactivation of SARS-CoV-2 Receptors: An In Silico Approach, Stresses, doi:10.3390/stresses3030043.
20.
Alkafaas et al., A study on the effect of natural products against the transmission of B.1.1.529 Omicron, Virology Journal, doi:10.1186/s12985-023-02160-6.
21.
Winih Kinasih et al., Analisis in silico interaksi senyawa kurkuminoid terhadap enzim main protease 6LU7 dari SARS-CoV-2, Duta Pharma Journal, doi:10.47701/djp.v3i1.2904.
22.
Wu (B) et al., Potential Mechanism of Curcumin and Resveratrol against SARS-CoV-2, Research Square, doi:10.21203/rs.3.rs-2780614/v1.
23.
Nag et al., Curcumin inhibits spike protein of new SARS-CoV-2 variant of concern (VOC) Omicron, an in silico study, Computers in Biology and Medicine, doi:10.1016/j.compbiomed.2022.105552.
24.
Rampogu et al., Molecular Docking and Molecular Dynamics Simulations Discover Curcumin Analogue as a Plausible Dual Inhibitor for SARS-CoV-2, International Journal of Molecular Sciences, doi:10.3390/ijms23031771.
25.
Singh (C) et al., Potential of turmeric-derived compounds against RNA-dependent RNA polymerase of SARS-CoV-2: An in-silico approach, Computers in Biology and Medicine, doi:10.1016/j.compbiomed.2021.104965.
26.
Kandeil et al., Bioactive Polyphenolic Compounds Showing Strong Antiviral Activities against Severe Acute Respiratory Syndrome Coronavirus 2, Pathogens, doi:10.3390/pathogens10060758.
27.
Rajagopal et al., Activity of phytochemical constituents of Curcuma longa (turmeric) and Andrographis paniculata against coronavirus (COVID-19): an in silico approach, Future Journal of Pharmaceutical Sciences, doi:10.1186/s43094-020-00126-x.
28.
Suravajhala et al., Comparative Docking Studies on Curcumin with COVID-19 Proteins, Preprints, doi:10.20944/preprints202005.0439.v3.
29.
Sekiou et al., In-Silico Identification of Potent Inhibitors of COVID-19 Main Protease (Mpro) and Angiotensin Converting Enzyme 2 (ACE2) from Natural Products: Quercetin, Hispidulin, and Cirsimaritin Exhibited Better Potential Inhibition than Hydroxy-Chloroquine Against COVID-19 Main Protease Active Site and ACE2, ChemRxiv, doi:10.26434/chemrxiv.12181404.v1.
30.
Aktay et al., Oral Administration of Water-Soluble Curcumin Complex Prevents ARDS With the Potential for COVID-19 Treatment, Phytotherapy Research, doi:10.1002/ptr.70046.
31.
Olubiyi et al., Novel dietary herbal preparations with inhibitory activities against multiple SARS-CoV-2 targets: A multidisciplinary investigation into antiviral activities, Food Chemistry Advances, doi:10.1016/j.focha.2025.100969.
32.
Emam et al., Establishment of in-house assay for screening of anti-SARS-CoV-2 protein inhibitors, AMB Express, doi:10.1186/s13568-024-01739-8.
33.
Van Tin et al., Spike Protein of SARS-CoV-2 Activates Cardiac Fibrogenesis through NLRP3 Inflammasomes and NF-κB Signaling, Cells, doi:10.3390/cells13161331.
34.
Li et al., Thermal shift assay (TSA)-based drug screening strategy for rapid discovery of inhibitors against the Nsp13 helicase of SARS-CoV-2, Animals and Zoonoses, doi:10.1016/j.azn.2024.06.001.
35.
Kamble et al., Nanoparticulate curcumin spray imparts prophylactic and therapeutic properties against SARS-CoV-2, Emergent Materials, doi:10.1007/s42247-024-00754-6.
36.
Nicoliche et al., Antiviral, anti-inflammatory and antioxidant effects of curcumin and curcuminoids in SH-SY5Y cells infected by SARS-CoV-2, Scientific Reports, doi:10.1038/s41598-024-61662-7.
37.
Nittayananta et al., A novel film spray containing curcumin inhibits SARS-CoV-2 and influenza virus infection and enhances mucosal immunity, Virology Journal, doi:10.1186/s12985-023-02282-x.
38.
Septisetyani et al., Curcumin and turmeric extract inhibited SARS-CoV-2 pseudovirus cell entry and Spike mediated cell fusion, bioRxiv, doi:10.1101/2023.09.28.560070.
39.
Mohd Abd Razak et al., In Vitro Anti-SARS-CoV-2 Activities of Curcumin and Selected Phenolic Compounds, Natural Product Communications, doi:10.1177/1934578X231188861.
40.
Fam et al., Channel activity of SARS-CoV-2 viroporin ORF3a inhibited by adamantanes and phenolic plant metabolites, Scientific Reports, doi:10.1038/s41598-023-31764-9.
41.
Teshima et al., Antiviral activity of curcumin and its analogs selected by an artificial intelligence-supported activity prediction system in SARS-CoV-2-infected VeroE6 cells, Natural Product Research, doi:10.1080/14786419.2023.2194647.
42.
Zupin et al., Optimization of Anti-SARS-CoV-2 Treatments Based on Curcumin, Used Alone or Employed as a Photosensitizer, Viruses, doi:10.3390/v14102132.
43.
Leka et al., In vitro antiviral activity against SARS-CoV-2 of common herbal medicinal extracts and their bioactive compounds, Phytotherapy Research, doi:10.1002/ptr.7463.
44.
Goc et al., Inhibitory effects of specific combination of natural compounds against SARS-CoV-2 and its Alpha, Beta, Gamma, Delta, Kappa, and Mu variants, European Journal of Microbiology and Immunology, doi:10.1556/1886.2021.00022.
45.
Marín-Palma et al., Curcumin Inhibits In Vitro SARS-CoV-2 Infection In Vero E6 Cells through Multiple Antiviral Mechanisms, Molecules, doi:10.3390/molecules26226900.
46.
Bahun et al., Inhibition of the SARS-CoV-2 3CLpro main protease by plant polyphenols, Food Chemistry, doi:10.1016/j.foodchem.2021.131594.
47.
Bormann et al., Turmeric Root and Its Bioactive Ingredient Curcumin Effectively Neutralize SARS-CoV-2 In Vitro, Viruses, doi:10.3390/v13101914.
a.
The trimeric spike (S) protein is a glycoprotein that mediates viral entry by binding to the host ACE2 receptor, is critical for SARS-CoV-2's ability to infect host cells, and is a target of neutralizing antibodies. Inhibition of the spike protein prevents viral attachment, halting infection at the earliest stage.
b.
The receptor binding domain is a specific region of the spike protein that binds ACE2 and is a major target of neutralizing antibodies. Focusing on the precise binding site allows highly specific disruption of viral attachment with reduced potential for off-target effects.
c.
The main protease or Mpro, also known as 3CLpro or nsp5, is a cysteine protease that cleaves viral polyproteins into functional units needed for replication. Inhibiting Mpro disrupts the SARS-CoV-2 lifecycle within the host cell, preventing the creation of new copies.
d.
RNA-dependent RNA polymerase (RdRp), also called nsp12, is the core enzyme of the viral replicase-transcriptase complex that copies the positive-sense viral RNA genome into negative-sense templates for progeny RNA synthesis. Inhibiting RdRp blocks viral genome replication and transcription.
e.
The papain-like protease (PLpro) has multiple functions including cleaving viral polyproteins and suppressing the host immune response by deubiquitination and deISGylation of host proteins. Inhibiting PLpro may block viral replication and help restore normal immune responses.
f.
The angiotensin converting enzyme 2 (ACE2) protein is a host cell transmembrane protein that serves as the cellular receptor for the SARS-CoV-2 spike protein. ACE2 is expressed on many cell types, including epithelial cells in the lungs, and allows the virus to enter and infect host cells. Inhibition may affect ACE2's physiological function in blood pressure control.
g.
The nucleocapsid (N) protein binds and encapsulates the viral genome by coating the viral RNA. N enables formation and release of infectious virions and plays additional roles in viral replication and pathogenesis. N is also an immunodominant antigen used in diagnostic assays.
h.
Non-structural protein 10 (nsp10) serves as an RNA chaperone and stabilizes conformations of nsp12 and nsp14 in the replicase-transcriptase complex, which synthesizes new viral RNAs. Nsp10 disruption may destabilize replicase-transcriptase complex activity.
i.
The helicase, or nsp13, protein unwinds the double-stranded viral RNA, a crucial step in replication and transcription. Inhibition may prevent viral genome replication and the creation of new virus components.
j.
The interaction between the SARS-CoV-2 spike protein and the human ACE2 receptor is a primary method of viral entry, inhibiting this interaction can prevent the virus from attaching to and entering host cells, halting infection at an early stage.
k.
Transmembrane protease serine 2 (TMPRSS2) is a host cell protease that primes the spike protein, facilitating cellular entry. TMPRSS2 activity helps enable cleavage of the spike protein required for membrane fusion and virus entry. Inhibition may especially protect respiratory epithelial cells, buy may have physiological effects.
l.
Calu-3 is a human lung adenocarcinoma cell line with moderate ACE2 and TMPRSS2 expression and SARS-CoV-2 susceptibility. It provides a model of the human respiratory epithelium, but many not be ideal for modeling early stages of infection due to the moderate expression levels of ACE2 and TMPRSS2.
m.
A549 is a human lung carcinoma cell line with low ACE2 expression and SARS-CoV-2 susceptibility. Viral entry/replication can be studied but the cells may not replicate all aspects of lung infection.
n.
293T is a human embryonic kidney cell line that can be engineered for high ACE2 expression and SARS-CoV-2 susceptibility. 293T cells are easily transfected and support high protein expression.
o.
HEK293-hACE2 is a human embryonic kidney cell line with high ACE2 expression and SARS-CoV-2 susceptibility. Cells have been transfected with a plasmid to express the human ACE2 (hACE2) protein.
p.
293T/hACE2/TMPRSS2 is a human embryonic kidney cell line engineered for high ACE2 and TMPRSS2 expression, which mimics key aspects of human infection. 293T/hACE2/TMPRSS2 cells are very susceptible to SARS-CoV-2 infection.
q.
Vero E6 is an African green monkey kidney cell line with low/no ACE2 expression and high SARS-CoV-2 susceptibility. The cell line is easy to maintain and supports robust viral replication, however the monkey origin may not accurately represent human responses.
r.
SH-SY5Y is a human neuroblastoma cell line that exhibits neuronal phenotypes. It is commonly used as an in vitro model for studying neurotoxicity, neurodegenerative diseases, and neuronal differentiation.
Wu et al., 2 Jun 2025, peer-reviewed, 7 authors.
Contact: wjy@stu.ymun.edu.cn, 410613031@gms.ndhu.edu.tw, r11454003@ntu.edu.tw, 202102410233@xmmc.edu.cn, mjtsai2@vghtpe.gov.tw, leong@gms.ndhu.edu.tw, 00435@ymun.edu.cn, cfweng@gms.ndhu.edu.tw.
In silico studies are an important part of preclinical research, however results may be very different in vivo.
Utilizing natural compounds as ligands to disrupt the binding of SARS-CoV-2 receptor-binding domain to angiotensin-converting enzyme 2, impeding viral infection
Phytochemistry Letters, doi:10.1016/j.phytol.2025.102999
Currently, no specific antiviral drug has been definitively proven effective in treating patients with severe coronavirus disease 2019 . Various specific strategies have been employed against COVID-19; however, several potent antiviral candidates, including prodrugs and repurposed drugs, are still under urgent investigation, particularly in the search for molecular targets. This study aimed to evaluate the potential of natural compounds and chemicals against RNA viruses using a three-tiered approach to molecular docking. Binding scores obtained from ChemPLP revealed that natural compounds and repurposed drugs exhibited strong affinities for the binding sites on angiotensin-converting enzyme 2 (ACE2) receptors in host cells, the receptorbinding domain (RBD) site of the RBD-ACE2 complex, PL pro , and 3CL pro . Conclusively, these findings suggest that alternative medicines and antiviral drug repurposing strategies may provide promising therapeutic remedies for patients with COVID-19, along with further validation via preclinical and clinical trials.
Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the respiratory illness that led to the coronavirus disease 2019 (COVID-19) pandemic, which began in late 2019 ( Acter et al., 2020) . The COVID-19 pandemic originated in December 2019 at the Seafood Market in Wuhan, China. The virus rapidly spread to Thailand, Japan, South Korea, Singapore, and Iran.
Declaration of Competing Interest The authors declare no conflict of interest.
Consent for publication All Authors listed have seen and approved the manuscript being submitted.
Appendix A. Supporting information Supplementary data associated with this article can be found in the online version at doi:10.1016/j.phytol.2025.102999.
References
Acter, Uddin, Das, Akhter, Choudhury et al., Evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as coronavirus disease 2019 (COVID-19) pandemic: a global health emergency, Sci. Total Environ, doi:10.1016/j.scitotenv.2020.138996
Agostini, Andres, Sims, Graham, Sheahan et al., Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease, mBio, doi:10.1128/mBio.00221-18
Alimohamadi, Rangamani, Modeling membrane curvature generation due to membrane(-)protein interactions, Biomolecules, doi:10.3390/biom8040120
Almen, Nordstrom, Fredriksson, Schioth, Mapping the human membrane proteome: a majority of the human membrane proteins can be classified according to function and evolutionary origin, BMC Biol, doi:10.1186/1741-7007-7-50
Andreou, Trantza, Filippou, Sipsas, Tsiodras, COVID-19: the potential role of copper and N-acetylcysteine (NAC) in a combination of candidate antiviral treatments against SARS-CoV-2 (3 Suppl), doi:10.21873/invivo.11946
Beigel, Tomashek, Dodd, Mehta, Zingman et al., Remdesivir for the treatment of COVID-19 -final report, N. Engl. J. Med, doi:10.1056/NEJMoa2007764
Brunotte, Zheng, Mecate-Zambrano, Tang, Ludwig et al., Combination therapy with fluoxetine and the nucleoside analog GS-441524 exerts synergistic antiviral effects against different SARS-CoV-2 variants in vitro, Pharmaceutics, doi:10.3390/pharmaceutics13091400
Chanput, Krueyos, Ritthiruangdej, Anti-oxidative assays as markers for anti-inflammatory activity of flavonoids, Int Immunopharmacol, doi:10.1016/j.intimp.2016.08.038
Cheng, Wang, Wang, Organ-protective effect of angiotensinconverting enzyme 2 and its effect on the prognosis of COVID-19, J. Med Virol, doi:10.1002/jmv.25785
Choy, Yin-Lam, Wong, Kaewpreedee, Sia et al., Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro, Antivir. Res, doi:10.1016/j.antiviral.2020.104786
Cui, Li, Shi, Origin and evolution of pathogenic coronaviruses, Nat. Rev. Microbiol, doi:10.1038/s41579-018-0118-9
De Wilde, Snijder, Kikkert, Van Hemert, Host factors in coronavirus replication, Curr. Top. Microbiol Immunol, doi:10.1007/82_2017_25
Donoghue, Hsieh, Baronas, Godbout, Gosselin et al., A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9, Circ. Res, doi:10.1161/01.res.87.5.e1
Elfiky, Ribavirin, remdesivir, sofosbuvir, galidesivir, and tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): a molecular docking study, Life Sci, doi:10.1016/j.lfs.2020.117592
Facente, Reiersen, Lenze, Boulware, Klausner, Fluvoxamine for the early treatment of SARS-CoV-2 infection: a review of current evidence, Drugs, doi:10.1007/s40265-021-01636-5
Gao, Tian, Yang, Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies, Biosci. Trends, doi:10.5582/bst.2020.01047
Jo, Kim, Shin, Kim, Inhibition of SARS-CoV 3CL protease by flavonoids, J. Enzym. Inhib. Med Chem, doi:10.1080/14756366.2019.1690480
Kalil, Patterson, Mehta, Tomashek, Wolfe et al., Baricitinib plus remdesivir for hospitalized adults with COVID-19, N. Engl. J. Med, doi:10.1056/NEJMoa2031994
Khuroo, Chloroquine and hydroxychloroquine in coronavirus disease 2019 (COVID-19). Facts, fiction and the hype: a critical appraisal, Int J. Antimicrob. Agents, doi:10.1016/j.ijantimicag.2020.106101
Kuba, Imai, Rao, Gao, Guo et al., A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury, Nat. Med, doi:10.1038/nm1267
Lan, 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/s41586-020-2180-5
Leong, Syu, Ding, Weng, Prediction of n-methyl-d-aspartate receptor glun1-ligand binding affinity by a novel svm-pose/svm-score combinatorial Ensemble Docking Scheme, Sci. Rep, doi:10.1038/srep40053
Li, Li, Farzan, Harrison, Structure of SARS coronavirus spike receptor-binding domain complexed with receptor, Science, doi:10.1126/science.1116480
Liu, Cao, Xu, Wang, Zhang et al., Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discov, doi:10.1038/s41421-020-0156-0
Luan, 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.2020.03.047
Mei, Zhou, Yang, Zhang, Liu et al., Active components in ephedra sinica stapf disrupt the interaction between ACE2 and SARS-CoV-2 RBD: Potent COVID-19 therapeutic agents, J. Ethnopharmacol, doi:10.1016/j.jep.2021.114303
Pang, Zhang, Bai, Wang, Garner et al., Attenuation of myocardial fibrosis with curcumin is mediated by modulating expression of angiotensin II AT1/AT2 receptors and ACE2 in rats, Drug Des. Dev. Ther, doi:10.2147/DDDT.S95333
Pasquini, Montalti, Temperoni, Canovari, Mancini et al., Effectiveness of remdesivir in patients with COVID-19 under mechanical ventilation in an Italian ICU, J. Antimicrob. Chemother, doi:10.1093/jac/dkaa321
Sargiacomo, Sotgia, Lisanti, COVID-19 and chronological aging: senolytics and other anti-aging drugs for the treatment or prevention of corona virus infection?, Aging, doi:10.18632/aging.103001
Simmons, Zmora, Gierer, Heurich, Pohlmann, Proteolytic activation of the SARS-coronavirus spike protein: cutting enzymes at the cutting edge of antiviral research, Antivir. Res, doi:10.1016/j.antiviral.2013.09.028
Sun, Chen, Fan, Wang, Han et al., Advances in the use of chloroquine and hydroxychloroquine for the treatment of COVID-19, Post. Med, doi:10.1080/00325481.2020.1778982
Wrapp, Wang, Corbett, Goldsmith, Hsieh et al., Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation, Science, doi:10.1126/science.abb2507
Zumla, Chan, Azhar, Hui, Yuen, Coronaviruses -drug discovery and therapeutic options, Nat. Rev. Drug Discov, doi:10.1038/nrd.2015.37
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