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Int J Biol Macromol ; 184: 297-312, 2021 Aug 01.
Article in English | MEDLINE | ID: covidwho-1265684


COVID-19 caused by SARS-CoV-2 corona virus has become a global pandemic. In the absence of drugs and vaccine, and premises of time, efforts and cost required for their development, natural resources such as herbs are anticipated to provide some help and may also offer a promising resource for drug development. Here, we have investigated the therapeutic prospective of Ashwagandha for the COVID-19 pandemic. Nine withanolides were tested in silico for their potential to target and inhibit (i) cell surface receptor protein (TMPRSS2) that is required for entry of virus to host cells and (ii) viral protein (the main protease Mpro) that is essential for virus replication. We report that the withanolides possess capacity to inhibit the activity of TMPRSS2 and Mpro. Furthermore, withanolide-treated cells showed downregulation of TMPRSS2 expression and inhibition of SARS-CoV-2 replication in vitro, suggesting that Ashwagandha may provide a useful resource for COVID-19 treatment.

Antiviral Agents/pharmacology , Plant Extracts/chemistry , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Viral Matrix Proteins/metabolism , Withanolides/pharmacology , A549 Cells , Antiviral Agents/chemistry , Cell Line , Cell Survival/drug effects , Computer Simulation , Down-Regulation , Gene Expression Regulation/drug effects , Humans , MCF-7 Cells , Models, Molecular , Molecular Dynamics Simulation , Protein Conformation , SARS-CoV-2/drug effects , Serine Endopeptidases/chemistry , Viral Matrix Proteins/chemistry , Virus Internalization/drug effects , Withanolides/chemistry
Drug Des Devel Ther ; 15: 1111-1133, 2021.
Article in English | MEDLINE | ID: covidwho-1150609


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.

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
J Mol Model ; 27(3): 97, 2021 Feb 28.
Article in English | MEDLINE | ID: covidwho-1103468


The spread of novel coronavirus SARS-CoV-2 has directed to a state of an unprecedented global pandemic. Many synthetic compounds and FDA-approved drugs have been significantly inhibitory against the virus, but no SARS-CoV-2 solution has been identified. However, small molecule fragment-based derivatives of potent phytocompounds may serve as promising inhibitors against SARS-CoV-2. In the pursuit of exploring novel SARS-CoV-2 inhibitors, we generated small molecule fragment derivatives from potent phytocompounds using neural networking and machine learning-based tools, which can cover unexplored regions of the chemical space that still retain lead-like properties. Out of 300 derivative molecules from withaferin-A, hesperidin, and baicalin, 30 were screened out with synthetic accessibility scores > 4 having the best ADME properties. The withaferin-A derivative molecules 61 and 64 exhibited a significant binding affinity of - 7.84 kcal/mol and - 7.94 kcal/mol. The docking study reveals that withaferin-A mol 61 forms 5 polar H-bonds with the Mpro where amino acids involved are GLU166, THR190, CYS145, MET165, and GLN152 and upon QSAR analysis showed a minimal predicted IC50 value of 7762.47 nM. Furthermore, the in silico cytotoxicity predictions, pharmacophore modeling, and molecular dynamics simulation studies have resulted in predicting the highly potent small molecule derivative from withaferin-A (phytocompound from Withania somnifera) to be the potential inhibitor of SARS-CoV 2 protease (Mpro) and a promising future lead candidate against COVID-19. The rationale of choosing withaferin-A from Withania somnifera (Ashwagandha) was propelled by the innumerous applications of Ashwagandha for the treatment of various antiviral diseases, common cold, and fever since time immemorial. Graphical abstract.

Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Withanolides/pharmacology , Antiviral Agents/chemistry , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Cell Line , Cell Line, Tumor , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Humans , Molecular Docking Simulation/methods , Molecular Dynamics Simulation , Protease Inhibitors/chemistry , Protein Binding , SARS-CoV-2/metabolism , Structure-Activity Relationship , Withanolides/chemistry