Background:Since the emergence of coronavirus disease 2019 to date,there is no available approved drug or definitive treatment for coronavirus disease 2019 viral infection,and the identification of novel hits against ...Background:Since the emergence of coronavirus disease 2019 to date,there is no available approved drug or definitive treatment for coronavirus disease 2019 viral infection,and the identification of novel hits against therapeutic targets has become a global emergency.Echinacea purpurea is a traditional herb utilized to treat cough,fever,sore throat,respiratory tract infection,and so on as an immune stimulant.In this study,in silico molecular docking approach was used to screen phytocompounds from E.purpurea against severe acute respiratory syndrome coronavirus 2 main protease 3C-like protease(3CLpro)and severe acute respiratory syndrome coronavirus main peptidase(96%sequence similarity)to blunt the viral gene expression and viral replication.Methods:Initially,we screened phytocompounds for their druggability and ADMET property.Furthermore,x-ray crystallographic structures of main proteases 3CLpro and main peptidase having Protein Data Bank ID 6LU7 and 2GTB were used as protein targets for the identification of potential drug candidates.We performed docking using AutoDock Vina by PyRx 0.8 software.BIOVIA Discovery Studio Visualizer v2019 was used to analyze ligand-protein complex.The probable protein targets of the selected compound were predicted by BindingDB(P≥0.7).STRING and Kyoto Encyclopedia of Genes and Genomes pathways are utilized to identify the molecular pathways modulated by the predicted targets(FDR≤0.05),and the network interaction between compounds and protein pathways was constructed by Cytoscape 3.6.1.Results:Among all the compounds,chlorogenic acid showed druggable characteristics and scored the lowest binding energy with main protease and main peptidase via interacting with active site 1 domain amino acid residues.Interestingly,chlorogenic acid interacted with Phe140 main protease 3CLpro,which is potentially involved in the dimerization.Enrichment analysis identified chlorogenic acid to modulate insulin resistance,necroptosis,interleukin-17,tumor necrosis factor signaling pathway,legionellosis,T helper 17 cell differentiation,advanced glycation end products and receptor for advanced glycation end products,mitogen-activated protein kinase,Ras,estrogen,vascular endothelial growth factor,B-cell receptor,nuclear factor kappa B,Rap1,hypoxia inducible factor-1,phosphatidylinositide 3-kinase-Akt,insulin,mechanistic target of rapamycin,p53,retinoic acid inducible gene I like receptor,and ErbB signaling pathways.Conclusion:Chlorogenic acid may act as a potent main protease 3CLpro inhibitor and may also inhibit the severe acute respiratory syndrome coronavirus 2 dimerization,viral gene expression,and replication within the lung epithelium.Chlorogenic acid may go a long way in finding one of the multipronged solutions to tackle coronavirus disease 2019 viral infection in the future.展开更多
Objective:To identify the safe and effective natural inhibitors of spike glycoprotein and main protease 3CLpro using potential natural antiviral compounds which are studied under various animal models and viral cell l...Objective:To identify the safe and effective natural inhibitors of spike glycoprotein and main protease 3CLpro using potential natural antiviral compounds which are studied under various animal models and viral cell lines.Methods:First,compounds were retrieved from the Pub Chem database and predicted for their druggability using the Mol Soft web server,and compounds having drug-like property were predicted for major adverse drug reactions like cardiotoxicity,hepatotoxicity,arrhythmia,myocardial infarction,and nephrotoxicity using ADVERpred.Docking of nontoxic antiviral compounds with spike glycoprotein and main protease 3CLpro was performed using Auto Dock vina by PyRx 0.8 version.The stability of compoundprotein interactions was checked by molecular dynamic(MD)simulation using Schrodinger Desmond software.Results:Based on the druggable and nontoxic profile,nine compounds were selected.Among them,Withanone from Withania somnifera showed the highest binding affinity and best fit at active sites 1 of spike glycoprotein(glycosylation site)and main protease 3CLpro via interacting with active site amino acid residues before and after MD simulation at 50 ns.Withanone,which may reduce the glycosylation of SARS-CoV-2 via interacting with Asn343 and inhibit viral replication.Conclusion:The current study reports Withanone as a non-toxic antiviral against SARS-CoV-2 and serve as a potential lead hit for further experimental validation.展开更多
3CL protease(3CLpro)is the main protease(Mpro)found in severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which cuts the coronavirus polyprotein at eleven conserved sites and is essential for the virus replic...3CL protease(3CLpro)is the main protease(Mpro)found in severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which cuts the coronavirus polyprotein at eleven conserved sites and is essential for the virus replication.Therefore,3CLpro has been widely used as a promising drug target.Many small-molecule drug candidates targeting 3CLpro have been proposed to inhibit the virus replication.In this work,we aim to reveal detailed interactions between ten small candidate molecules with extensive attention and 3CLpro using molecular docking and molecular dynamics simulations.First,we identified the possible binding sites of these candidate molecules on 3CLpro via molecular docking.Then,a series of 100 ns all-atom molecular dynamics simulations of strongest binding modes were performed to further evaluate the dynamical interactions between the molecules and 3CLpro in detail.Last,the binding free energy of these molecules on 3CLpro was calculated using MM/PBSA calculation,where the contribution of key amino acids was highlighted.The binding kinetics revealed in this work may provide useful insights into the action mechanism and applicability of these small-molecule drug candidates.展开更多
Anthraquinone derivatives are identified for their immune-boosting,anti-inflammatory,and anti-viral efficacy.Hence,the pre-sent study aimed to investigate the reported anthraquinone derivatives as immune booster molec...Anthraquinone derivatives are identified for their immune-boosting,anti-inflammatory,and anti-viral efficacy.Hence,the pre-sent study aimed to investigate the reported anthraquinone derivatives as immune booster molecules in COVID-19 infection and evaluate their binding affinity with three reported targets of novel coronavirus i.e.3C-like protease,papain-like protease,and spike protein.The reported anthraquinone derivatives were retrieved from an open-source database and filtered based on a positive druglikeness score.Compounds with positive druglikeness scores were predicted for their targets using DIGEP-Pred and the interaction among modulated proteins was evaluated using STRING.Further,the associated pathways were recorded concerning the Kyoto Encyclopedia of Genes and Genomes pathway database.Finally,the docking was performed using autodock4 to identify the binding efficacy of anthraquinone derivatives with 3C-like protease,papain-like protease,and spike protein.After docking the pose of ligand scoring minimum binding energy was chosen to visualize the ligand-protein interaction.Among 101 bioactives,36 scored positive druglikeness score and regulated multiple pathways concerned with immune modulation and(non-)infectious diseases.Similarly,docking study revealed torososide B to possess the highest binding affinity with papain-like protease and 3C-like protease and 1,3,6-trihydroxy-2-methyl-9,10-anthraquinone-3-O-(6′-O-acetyl)-β-d-xylopyranosyl-(1→2)-β-d-glucopyranoside with spike protein.展开更多
There are only eight approved small molecule antiviral drugs for treating COVID-19.Among them,four are nucleotide analogues(remdesivir,JT001,molnupiravir,and azvudine),while the other four are protease inhibitors(nirm...There are only eight approved small molecule antiviral drugs for treating COVID-19.Among them,four are nucleotide analogues(remdesivir,JT001,molnupiravir,and azvudine),while the other four are protease inhibitors(nirmatrelvir,ensitrelvir,leritrelvir,and simnotrelvir-ritonavir).Antiviral resistance,unfavourable drug‒drug interaction,and toxicity have been reported in previous studies.Thus there is a dearth of new treatment options for SARS-CoV-2.In this work,a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-CoV-2 activity.One compound,designated 172,demonstrated broad-spectrum antiviral activity against multiple human pathogenic coronaviruses and different SARS-CoV-2 variants of concern.Mechanistic studies validated by reverse genetics showed that compound 172 inhibits the 3-chymotrypsin-like protease(3CLpro)by binding to an allosteric site and reduces 3CLpro dimerization.A drug synergistic checkerboard assay demonstrated that compound 172 can achieve drug synergy with nirmatrelvir in vitro.In vivo studies confirmed the antiviral activity of compound 172 in both Golden Syrian Hamsters and K18 humanized ACE2 mice.Overall,this study identified an alternative druggable site on the SARS-CoV-23CLpro,proposed a potential combination therapy with nirmatrelvir to reduce the risk of antiviral resistance and shed light on the development of allosteric protease inhibitors for treating a range of coronavirus diseases.展开更多
The active site of 3CL proteinase (3CLpro) for coronavirus was identified by comparing the crystal structures of human and porcine coronavirus. The inhibitor of the main protein of rhinovirus (Ag7088) could bind with...The active site of 3CL proteinase (3CLpro) for coronavirus was identified by comparing the crystal structures of human and porcine coronavirus. The inhibitor of the main protein of rhinovirus (Ag7088) could bind with 3CLpro of human coronavirus, then it was selected as the reference for molecular docking and database screening. The ligands from two databases were used to search potential lead structures with molecular docking. Several structures from natural products and ACD-SC databases were found to have lower binding free energy with 3CLpro than that of Ag7088. These structures have similar hydrophobicity to Ag7088. They have complementary electrostatic potential and hydrogen bond acceptor and donor with 3CLpro, showing that the strategy of anti-SARS drug design based on molecular docking and database screening is feasible.展开更多
文摘Background:Since the emergence of coronavirus disease 2019 to date,there is no available approved drug or definitive treatment for coronavirus disease 2019 viral infection,and the identification of novel hits against therapeutic targets has become a global emergency.Echinacea purpurea is a traditional herb utilized to treat cough,fever,sore throat,respiratory tract infection,and so on as an immune stimulant.In this study,in silico molecular docking approach was used to screen phytocompounds from E.purpurea against severe acute respiratory syndrome coronavirus 2 main protease 3C-like protease(3CLpro)and severe acute respiratory syndrome coronavirus main peptidase(96%sequence similarity)to blunt the viral gene expression and viral replication.Methods:Initially,we screened phytocompounds for their druggability and ADMET property.Furthermore,x-ray crystallographic structures of main proteases 3CLpro and main peptidase having Protein Data Bank ID 6LU7 and 2GTB were used as protein targets for the identification of potential drug candidates.We performed docking using AutoDock Vina by PyRx 0.8 software.BIOVIA Discovery Studio Visualizer v2019 was used to analyze ligand-protein complex.The probable protein targets of the selected compound were predicted by BindingDB(P≥0.7).STRING and Kyoto Encyclopedia of Genes and Genomes pathways are utilized to identify the molecular pathways modulated by the predicted targets(FDR≤0.05),and the network interaction between compounds and protein pathways was constructed by Cytoscape 3.6.1.Results:Among all the compounds,chlorogenic acid showed druggable characteristics and scored the lowest binding energy with main protease and main peptidase via interacting with active site 1 domain amino acid residues.Interestingly,chlorogenic acid interacted with Phe140 main protease 3CLpro,which is potentially involved in the dimerization.Enrichment analysis identified chlorogenic acid to modulate insulin resistance,necroptosis,interleukin-17,tumor necrosis factor signaling pathway,legionellosis,T helper 17 cell differentiation,advanced glycation end products and receptor for advanced glycation end products,mitogen-activated protein kinase,Ras,estrogen,vascular endothelial growth factor,B-cell receptor,nuclear factor kappa B,Rap1,hypoxia inducible factor-1,phosphatidylinositide 3-kinase-Akt,insulin,mechanistic target of rapamycin,p53,retinoic acid inducible gene I like receptor,and ErbB signaling pathways.Conclusion:Chlorogenic acid may act as a potent main protease 3CLpro inhibitor and may also inhibit the severe acute respiratory syndrome coronavirus 2 dimerization,viral gene expression,and replication within the lung epithelium.Chlorogenic acid may go a long way in finding one of the multipronged solutions to tackle coronavirus disease 2019 viral infection in the future.
文摘Objective:To identify the safe and effective natural inhibitors of spike glycoprotein and main protease 3CLpro using potential natural antiviral compounds which are studied under various animal models and viral cell lines.Methods:First,compounds were retrieved from the Pub Chem database and predicted for their druggability using the Mol Soft web server,and compounds having drug-like property were predicted for major adverse drug reactions like cardiotoxicity,hepatotoxicity,arrhythmia,myocardial infarction,and nephrotoxicity using ADVERpred.Docking of nontoxic antiviral compounds with spike glycoprotein and main protease 3CLpro was performed using Auto Dock vina by PyRx 0.8 version.The stability of compoundprotein interactions was checked by molecular dynamic(MD)simulation using Schrodinger Desmond software.Results:Based on the druggable and nontoxic profile,nine compounds were selected.Among them,Withanone from Withania somnifera showed the highest binding affinity and best fit at active sites 1 of spike glycoprotein(glycosylation site)and main protease 3CLpro via interacting with active site amino acid residues before and after MD simulation at 50 ns.Withanone,which may reduce the glycosylation of SARS-CoV-2 via interacting with Asn343 and inhibit viral replication.Conclusion:The current study reports Withanone as a non-toxic antiviral against SARS-CoV-2 and serve as a potential lead hit for further experimental validation.
基金the National Natural Science Foundation of China(No.21903002)the Fundamental Research Funds for the Central Universities(No.YWF-22-L-629).
文摘3CL protease(3CLpro)is the main protease(Mpro)found in severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which cuts the coronavirus polyprotein at eleven conserved sites and is essential for the virus replication.Therefore,3CLpro has been widely used as a promising drug target.Many small-molecule drug candidates targeting 3CLpro have been proposed to inhibit the virus replication.In this work,we aim to reveal detailed interactions between ten small candidate molecules with extensive attention and 3CLpro using molecular docking and molecular dynamics simulations.First,we identified the possible binding sites of these candidate molecules on 3CLpro via molecular docking.Then,a series of 100 ns all-atom molecular dynamics simulations of strongest binding modes were performed to further evaluate the dynamical interactions between the molecules and 3CLpro in detail.Last,the binding free energy of these molecules on 3CLpro was calculated using MM/PBSA calculation,where the contribution of key amino acids was highlighted.The binding kinetics revealed in this work may provide useful insights into the action mechanism and applicability of these small-molecule drug candidates.
文摘Anthraquinone derivatives are identified for their immune-boosting,anti-inflammatory,and anti-viral efficacy.Hence,the pre-sent study aimed to investigate the reported anthraquinone derivatives as immune booster molecules in COVID-19 infection and evaluate their binding affinity with three reported targets of novel coronavirus i.e.3C-like protease,papain-like protease,and spike protein.The reported anthraquinone derivatives were retrieved from an open-source database and filtered based on a positive druglikeness score.Compounds with positive druglikeness scores were predicted for their targets using DIGEP-Pred and the interaction among modulated proteins was evaluated using STRING.Further,the associated pathways were recorded concerning the Kyoto Encyclopedia of Genes and Genomes pathway database.Finally,the docking was performed using autodock4 to identify the binding efficacy of anthraquinone derivatives with 3C-like protease,papain-like protease,and spike protein.After docking the pose of ligand scoring minimum binding energy was chosen to visualize the ligand-protein interaction.Among 101 bioactives,36 scored positive druglikeness score and regulated multiple pathways concerned with immune modulation and(non-)infectious diseases.Similarly,docking study revealed torososide B to possess the highest binding affinity with papain-like protease and 3C-like protease and 1,3,6-trihydroxy-2-methyl-9,10-anthraquinone-3-O-(6′-O-acetyl)-β-d-xylopyranosyl-(1→2)-β-d-glucopyranoside with spike protein.
基金National Natural Science Foundation of China(NSFC)/Research Grants Council(RGC)Joint Research Scheme(N_HKU767/22 and 82261160398)Health and Medical Research Fund(COVID190121)+13 种基金the Food and Health Bureau,The Government of the Hong Kong Special Administrative Regionthe National Natural Science Foundation of China(32322087,32300134,and 82272337)Guangdong Natural Science Foundation(2023A1515012907)Health@-InnoHK,Innovation and Technology Commission,the Government of the Hong Kong Special Administrative Regionthe Collaborative Research Fund(C7060-21G and C7002-23Y)and Theme-Based Research Scheme(T11-709/21-N)of the Research Grants Council,The Government of the Hong Kong Special Administrative RegionPartnership Programme of Enhancing Laboratory Surveillance and Investigation of Emerging Infectious Diseases and Antimicrobial Resistance for the Department of Health of the Hong Kong Special Administrative Region GovernmentSanming Project of Medicine in Shenzhen,China(SZSM201911014)the High Level-Hospital Program,Health Commission of Guangdong Province,Chinathe research project of Hainan Academician Innovation Platform(YSPTZX202004)Emergency Collaborative Project of Guangzhou Laboratory(EKPG22-01)and the National Key R&D Program of China(projects 2021YFC0866100 and 2023YFC3041600)The University of Hong Kong Seed Fund for Collaborative Research(2207101537)and Hunan University(521119400156)donations of Providence Foundation Limited(in memory of the late Lui Hac Minh).
文摘There are only eight approved small molecule antiviral drugs for treating COVID-19.Among them,four are nucleotide analogues(remdesivir,JT001,molnupiravir,and azvudine),while the other four are protease inhibitors(nirmatrelvir,ensitrelvir,leritrelvir,and simnotrelvir-ritonavir).Antiviral resistance,unfavourable drug‒drug interaction,and toxicity have been reported in previous studies.Thus there is a dearth of new treatment options for SARS-CoV-2.In this work,a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-CoV-2 activity.One compound,designated 172,demonstrated broad-spectrum antiviral activity against multiple human pathogenic coronaviruses and different SARS-CoV-2 variants of concern.Mechanistic studies validated by reverse genetics showed that compound 172 inhibits the 3-chymotrypsin-like protease(3CLpro)by binding to an allosteric site and reduces 3CLpro dimerization.A drug synergistic checkerboard assay demonstrated that compound 172 can achieve drug synergy with nirmatrelvir in vitro.In vivo studies confirmed the antiviral activity of compound 172 in both Golden Syrian Hamsters and K18 humanized ACE2 mice.Overall,this study identified an alternative druggable site on the SARS-CoV-23CLpro,proposed a potential combination therapy with nirmatrelvir to reduce the risk of antiviral resistance and shed light on the development of allosteric protease inhibitors for treating a range of coronavirus diseases.
基金Project supported by the Minister of Science and Technology of China (Nos. 2003CB114401 and 2002AA231011) the National Natural ScienceFoundation of China (No. 20073058)+1 种基金 Science and Technology Committee of Shanghai (No. 02DJ14013) Chinese Academy
文摘The active site of 3CL proteinase (3CLpro) for coronavirus was identified by comparing the crystal structures of human and porcine coronavirus. The inhibitor of the main protein of rhinovirus (Ag7088) could bind with 3CLpro of human coronavirus, then it was selected as the reference for molecular docking and database screening. The ligands from two databases were used to search potential lead structures with molecular docking. Several structures from natural products and ACD-SC databases were found to have lower binding free energy with 3CLpro than that of Ag7088. These structures have similar hydrophobicity to Ag7088. They have complementary electrostatic potential and hydrogen bond acceptor and donor with 3CLpro, showing that the strategy of anti-SARS drug design based on molecular docking and database screening is feasible.
