Identification of bioactive molecules from Triphala (Ayurvedic herbal formulation) as potential inhibitors of SARS-CoV-2 main protease (Mpro) through computational investigations.

Severe acute respiratory syndrome coronavirus disease (SARS-CoV-2) induced coronavirus disease 2019 (COVID-19) pandemic is the present worldwide health emergency. The global scientific community faces a significant challenge in developing targeted therapies to combat the SARS-CoV-2 infection. Computational approaches have been critical for identifying potential SARS-CoV-2 inhibitors in the face of limited resources and in this time of crisis. Main protease (Mpro) is an intriguing drug target because it processes the polyproteins required for SARS-CoV-2 replication. The application of Ayurvedic knowledge from traditional Indian systems of medicine may be a promising strategy to develop potential inhibitor for different target proteins of SARS-CoV-2. With this endeavor, we docked bioactive molecules from Triphala, an Ayurvedic formulation, against Mpro followed by molecular dynamics (MD) simulation (100 ns) to investigate their inhibitory potential against SARS-CoV-2. The top four best docked molecules (terflavin A, chebulagic acid, chebulinic acid, and corilagin) were selected for MD simulation study and the results obtained were compared to native ligand X77. From docking and MD simulation studies, the selected molecules showed promising binding affinity with the formation of stable complexes at the active binding pocket of Mpro and exhibited negative binding energy during MM-PBSA calculations, indication their strong binding affinity with the target protein. The identified bioactive molecules were further analyzed for drug-likeness by Lipinski's filter, ADMET and toxicity studies. Computational (in silico) investigations identified terflavin A, chebulagic acid, chebulinic acid, and corilagin from Triphala formulation as promising inhibitors of SARS-CoV-2 Mpro, suggesting experimental (in vitro/in vivo) studies to further explore their inhibitory mechanisms.

Host Cell and SARS-CoV-2-Associated Molecular Structures and Factors as Potential Therapeutic Targets.

Coronavirus disease 19 (COVID-19) is caused by an enveloped, positive-sense, single-stranded RNA virus, referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to the realm Riboviria, order Nidovirales, family Coronaviridae, genus Betacoronavirus and the species Severe acute respiratory syndrome-related coronavirus. This viral disease is characterized by a myriad of varying symptoms, such as pyrexia, cough, hemoptysis, dyspnoea, diarrhea, muscle soreness, dysosmia, lymphopenia and dysgeusia amongst others. The virus mainly infects humans, various other mammals, avian species and some other companion livestock. SARS-CoV-2 cellular entry is primarily accomplished by molecular interaction between the virus's spike (S) protein and the host cell surface receptor, angiotensin-converting enzyme 2 (ACE2), although other host cell-associated receptors/factors, such as neuropilin 1 (NRP-1) and neuropilin 2 (NRP-2), C-type lectin receptors (CLRs), as well as proteases such as TMPRSS2 (transmembrane serine protease 2) and furin, might also play a crucial role in infection, tropism, pathogenesis and clinical outcome. Furthermore, several structural and non-structural proteins of the virus themselves are very critical in determining the clinical outcome following infection. Considering such critical role(s) of the abovementioned host cell receptors, associated proteases/factors and virus structural/non-structural proteins (NSPs), it may be quite prudent to therapeutically target them through a multipronged clinical regimen to combat the disease.

In silico screening of hundred phytocompounds of ten medicinal plants as potential inhibitors of nucleocapsid phosphoprotein of COVID-19: an approach to prevent virus assembly.

Currently, there is no specific treatment to cure COVID-19. Many medicinal plants have antiviral, antioxidant, antibacterial, antifungal, anticancer, wound healing etc. Therefore, the aim of the current study was to screen for potent inhibitors of N-terminal domain (NTD) of nucleocapsid phosphoprotein of SARS-CoV-2. The structure of NTD of RNA binding domain of nucleocapsid phosphoprotein of SARS coronavirus 2 was retrieved from the Protein Data Bank (PDB 6VYO) and the structures of 100 different phytocompounds were retrieved from Pubchem. The receptor protein and ligands were prepared using Schrodinger's Protein Preparation Wizard. Molecular docking was done by using the Schrodinger's maestro 12.0 software. Drug likeness and toxicity of active phytocompounds was predicted by using Swiss adme, admetSAR and protox II online servers. Molecular dynamic simulation of the best three protein- ligand complexes (alizarin, aloe-emodin and anthrarufin) was performed to study the interaction stability. We have identified three potential active sites (named as A, B, C) on receptor protein for efficient binding of the phytocompounds. We found that, among 100 phytocompounds, emodin, aloe-emodin, anthrarufin, alizarine, and dantron of Rheum emodi showed good binding affinity at all the three active sites of RNA binding domain of nucleocapsid phosphoprotein of COVID-19.The binding energies of emodin, aloe-emodin, anthrarufin, alizarine, and dantron were -8.299, -8.508, -8.456, -8.441, and -8.322 Kcal mol-1 respectively (site A), -7.714, -6.433, -6.354, -6.598, and -6.99 Kcal mol-1 respectively (site B), and -8.299, 8.508, 8.538, 8.841, and 8.322 Kcal mol-1 respectively (site C). All the active phytocompounds follows the drug likeness properties, non-carcinogenic, and non-toxic. Theses phytocompounds (alone or in combination) could be developed into effective therapy against COVID-19. From MD simulation data, we found that all three complexes of 6VYO with alizarin, aloe-emodin and anthrarufin were stable up to 50 ns. These phytocompounds can be tested further for in vitro or in vivo and used as a potential drug to cure SARS-CoV-2 infection.Communicated by Ramaswamy H. Sarma.