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1.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-306211

ABSTRACT

Background: Newly emerged COVID-19 has been shown to engage the host cell ACE2 through its spike protein receptor binding domain (RBD). Here we show that natural phytochemical from a medicinal herb, Withania somnifera, have distinct effects on viral RBD and host ACE2 receptor complex. Methods We employed molecular docking to screen thousands of phytochemicals against the ACE2-RBD complex, performed molecular dynamics (MD) simulation, and estimated the electrostatic component of binding free energy, along with the computation of salt bridge electrostatics. Results We report that W. somnifera compound, Withanone, docked very well in the binding interface of AEC2-RBD complex, and was found to move slightly towards the interface centre on simulation. Withanone significantly decreased electrostatic component of binding free energies of ACE2-RBD complex. Two salt bridges were also identified at the interface;incorporation of Withanone destabilized these salt bridges and decreased their occupancies. We postulate, such an interruption of electrostatic interactions between the RBD and ACE2 would block or weaken COVID-19 entry and its subsequent infectivity. Conclusion Our data, for the first time, show that natural phytochemicals could well be the viable options for controlling COVID-19 entry into host cells, and W. somnifera may be the first choice of herbs in these directions to curb the COVID-19 infectivity.

2.
Drug Des Devel Ther ; 15: 1111-1133, 2021.
Article in English | MEDLINE | ID: covidwho-1150609

ABSTRACT

PURPOSE: SARS-CoV-2 engages human ACE2 through its spike (S) protein receptor binding domain (RBD) to enter the host cell. Recent computational studies have reported that withanone and withaferin A, phytochemicals found in Withania somnifera, target viral main protease (MPro) and host transmembrane TMPRSS2, and glucose related protein 78 (GRP78), respectively, implicating their potential as viral entry inhibitors. Absence of specific treatment against SARS-CoV-2 infection has encouraged exploration of phytochemicals as potential antivirals. AIM: This study aimed at in silico exploration, along with in vitro and in vivo validation of antiviral efficacy of the phytochemical withanone. METHODS: Through molecular docking, molecular dynamic (MD) simulation and electrostatic energy calculation the plausible biochemical interactions between withanone and the ACE2-RBD complex were investigated. These in silico observations were biochemically validated by ELISA-based assays. Withanone-enriched extract from W. somnifera was tested for its ability to ameliorate clinically relevant pathological features, modelled in humanized zebrafish through SARS-CoV-2 recombinant spike (S) protein induction. RESULTS: Withanone bound efficiently at the interacting interface of the ACE2-RBD complex and destabilized it energetically. The electrostatic component of binding free energies of the complex was significantly decreased. The two intrachain salt bridge interactions (K31-E35) and the interchain long-range ion-pair (K31-E484), at the ACE2-RBD interface were completely abolished by withanone, in the 50 ns simulation. In vitro binding assay experimentally validated that withanone efficiently inhibited (IC50=0.33 ng/mL) the interaction between ACE2 and RBD, in a dose-dependent manner. A withanone-enriched extract, without any co-extracted withaferin A, was prepared from W. somnifera leaves. This enriched extract was found to be efficient in ameliorating human-like pathological responses induced in humanized zebrafish by SARS-CoV-2 recombinant spike (S) protein. CONCLUSION: In conclusion, this study provided experimental validation for computational insight into the potential of withanone as a potent inhibitor of SARS-CoV-2 coronavirus entry into the host cells.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , COVID-19/drug therapy , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Withania , Withanolides/pharmacology , A549 Cells , Animals , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , COVID-19/enzymology , COVID-19/virology , Disease Models, Animal , Female , Host-Pathogen Interactions , Humans , Male , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Interaction Domains and Motifs , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/chemistry , Static Electricity , Structure-Activity Relationship , Virus Internalization/drug effects , Withania/chemistry , Withanolides/chemistry , Withanolides/isolation & purification , Zebrafish
3.
Curr Mol Med ; 2021 Feb 17.
Article in English | MEDLINE | ID: covidwho-1090485

ABSTRACT

BACKGROUND: Strategy to inhibit the virus replication is an attractive means in combating SARS-CoV-2 infection. OBJECTIVE: We studied phyto-compounds from Strychnos nux-vomica (a poisonous plant) against SARS-CoV-2 RNA-dependent RNA polymerase by computational methods. METHOD: Molecular docking, molecular dynamics (MD) simulation and energetics calculations were employed to elucidate the role of the phyto-compounds. RESULTS: Ergotamine with a binding free energy of -14.39 kcal/mol showed a promising capability in terms of both the binding affinity and interacting to conserved motifs, especially the SDD signature sequence. The calculated dissociation constants for ATP, ergotamine, isosungucine and sungucine were 12 µM, 0.072 nM, 0.011 nM and 0.152 nM, respectively. The exhibited kd by these phyto-compounds reflected a tens of thousands fold potency as compared to ATP. The binding free energies of sungucine and isosungucine were much lower (-13.93 and -15.55 kcal/mol, respectively) compared to that of ATP (-6.98 kcal/mol). CONCLUSION: Sharing the same binding location as that of ATP and having high binding affinities, Ergotamine, Isosungucine, Sungucine and Strychnine N-oxide could be effective in controlling the SARS-CoV-2 virus replication by blocking the ATP and inhibiting the enzyme function.

4.
Comb Chem High Throughput Screen ; 24(10): 1795-1802, 2021.
Article in English | MEDLINE | ID: covidwho-918979

ABSTRACT

BACKGROUND: SARS-CoV-2 has been shown to bind the host cell ACE2 receptor through its spike protein receptor binding domain (RBD), required for its entry into the host cells. OBJECTIVE: We have screened phytocompounds from a medicinal herb, Tinospora cordifolia for their capacities to interrupt the viral RBD and host ACE2 interactions. METHODS: We employed molecular docking to screen phytocompounds in T. cordifolia against the ACE2-RBD complex, performed molecular dynamics (MD) simulation, and estimated the electrostatic component of binding free energy. RESULTS: 'Tinocordiside' docked very well at the center of the interface of ACE2-RBD complex, and was found to be well stabilized during MD simulation. Tinocordiside incorporation significantly decreased the electrostatic component of binding free energies of the ACE2-RBD complex (23.5 and 17.10 kcal/mol in the trajectories without or with the ligand, respectively). As the basal rate constant of protein association is in the order of 5 (105 to 106 M-1S-1), there might be no big conformational change or loop reorganization, but involves only local conformational change typically observed in the diffusion-controlled association. Taken together, the increase in global flexibility of the complex clearly indicates the start of unbinding process of the complex. CONCLUSION: It indicates that such an interruption of electrostatic interactions between the RBD and ACE2, and the increase in global flexibility of the complex would weaken or block SARSCoV- 2 entry and its subsequent infectivity. We postulate that natural phytochemicals like Tinocordiside could be viable options for controlling SARS-CoV-2 contagion and its entry into host cells.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , Antiviral Agents/pharmacology , Glycosides/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/chemistry , Tinospora/chemistry , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Gene Expression , Glycosides/chemistry , Glycosides/isolation & purification , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , Kinetics , Molecular Docking Simulation , Molecular Dynamics Simulation , Plant Extracts/chemistry , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , SARS-CoV-2/growth & development , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Static Electricity , Thermodynamics , Virus Internalization/drug effects
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