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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
J Biomol Struct Dyn ; 40(1): 1-13, 2022 01.
Article in English | MEDLINE | ID: covidwho-436584


Coronavirus disease 2019 (COVID-19) initiated in December 2019 in Wuhan, China and became pandemic causing high fatality and disrupted normal life calling world almost to a halt. Causative agent is a novel coronavirus called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2/2019-nCoV). While new line of drug/vaccine development has been initiated world-wide, in the current scenario of high infected numbers, severity of the disease and high morbidity, repurposing of the existing drugs is heavily explored. Here, we used a homology-based structural model of transmembrane protease serine 2 (TMPRSS2), a cell surface receptor, required for entry of virus to the target host cell. Using the strengths of molecular docking and molecular dynamics simulations, we examined the binding potential of Withaferin-A (Wi-A), Withanone (Wi-N) and caffeic acid phenethyl ester to TPMRSS2 in comparison to its known inhibitor, Camostat mesylate. We found that both Wi-A and Wi-N could bind and stably interact at the catalytic site of TMPRSS2. Wi-N showed stronger interactions with TMPRSS2 catalytic residues than Wi-A and was also able to induce changes in its allosteric site. Furthermore, we investigated the effect of Wi-N on TMPRSS2 expression in MCF7 cells and found remarkable downregulation of TMPRSS2 mRNA in treated cells predicting dual action of Wi-N to block SARS-CoV-2 entry into the host cells. Since the natural compounds are easily available/affordable, they may even offer a timely therapeutic/preventive value for the management of SARS-CoV-2 pandemic. We also report that Wi-A/Wi-N content varies in different parts of Ashwagandha and warrants careful attention for their use.Communicated by Ramaswamy H. Sarma.

SARS-CoV-2 , Serine Proteinase Inhibitors/pharmacology , Virus Internalization/drug effects , Withanolides/pharmacology , Binding Sites , COVID-19 , Humans , MCF-7 Cells , Molecular Docking Simulation , Plant Extracts/chemistry , Serine , Serine Endopeptidases/genetics