Artecanin of Laurus nobilis is a novel inhibitor of SARS-CoV-2 main protease with highly desirable druglikeness.

Main protease (Mpro) is a critical enzyme in the life cycle of severe acute respiratory syndrome Coronavirus -2 (SARS-CoV-2). Due to its essential role in the maturation of the polyproteins, the necessity to inhibit Mpro is one of the essential means to prevent the outbreak of COVID-19. In this context, this study was conducted on the natural compounds of medicinal plants that are commonly available in the Middle East to find out the most potent one to inhibit Mpro with the best bioavailability and druglikeness properties. A total of 3392 compounds of sixty-six medicinal plants were retrieved from PubChem database and docked against Mpro. Thirty compounds with the highest docking scores with Mpro were chosen for further virtual screening. Variable druglikeness and toxicity potentials of these compounds were evaluated using SwissADME and Protox servers respectively. Out of these virtually screened compounds, artecanin was predicted to exhibit the most favourable druglikeness potentials, accompanied by no predicted hepatoxicity, carcinogenicity, mutagenicity, and cytotoxicity. Molecular dynamics (MD) simulations showed that Mpro-artecanin complex exhibited comparable stability with that observed in the ligand-free Mpro. This study revealed for the first time that artecanin from Laurus nobilis provided a novel static and dynamic inhibition for Mpro with excellent safety, oral bioavailability, and pharmacokinetic profile. This study suggested the ability of artecanin to be used as a potential natural inhibitor that can be used to block or at least counteract the SARS-CoV-2 invasion.Communicated by Ramaswamy H. Sarma.

Pharmacophore-Based Virtual Screening of Potential SARS-CoV-2 Main Protease Inhibitors from Library of Natural Products

Background: The SARS-CoV-2 main protease (Mpro) is an attractive target for drug discovery. Method(s): A pharmacophore model was built using the three-dimensional (3D) pharmacophore generation algorithm HypoGen in Discovery Studio 2019. The best pharmacophore model was selected for validation using a test set of 24 compounds and was used as a 3D query for further screening of an in-house database of natural compounds. Lipinski's rule of five was used to assess the drug-like properties of the hit compounds. The filtered compounds were then subjected to bioactivity evaluations. The active compounds were docked into the active site of the SARS-CoV-2 Mpro crystal structure (PDB ID: 7D1M). Result(s): A suitable 3D pharmacophore model, Hypo1, was found to be the best model, consisting of four features (one hydrophobic feature, one hydrogen bond donor, and two hydrogen bond acceptors). Pharmacophore-based virtual screening with Hypo1 as the query to search an in-house database of 34 439 natural compounds resulted in 1502 hits. Among these, 255 compounds satisfied Lipinski's rule of five. The highest ranking 10 compounds were selected for further experimental testing, and one hit (W-7) illustrated inhibitory activity against SARS-CoV-2 Mpro with an IC50 value of 75 muM. Docking studies revealed that this hit compound retained the necessary interactions within the active site of SARS-CoV-2 Mpro. Conclusion The identified lead natural compound could provide a scaffold for the further development of SARS-CoV-2 Mpro inhibitors. Copyright © The Author(s) 2022.

Natural inhibitors of SARS-CoV-2 main protease: structure based pharmacophore modeling, molecular docking and molecular dynamic simulation studies.

Main protease (Mpro) plays a key role in replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study was designed for finding natural inhibitors of SARS-CoV-2 Mpro by in silico methods. To this end, the co-crystal structure of Mpro with telaprevir was explored and receptor-ligand pharmacophore models were developed and validated using pharmit. The database of "ZINC Natural Products" was screened, and 288 compounds were filtered according to pharmacophore features. In the next step, Lipinski's rule of five was applied and absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the filtered compounds were calculated using in silico methods. The resulted 15 compounds were docked into the active site of Mpro and those with the highest binding scores and better interaction including ZINC61991204, ZINC67910260, ZINC61991203, and ZINC08790293 were selected. Further analysis by molecular dynamic simulation studies showed that ZINC61991203 and ZINC08790293 dissociated from Mpro active site, while ZINC426421106 and ZINC5481346 were stable. Root mean square deviation (RMSD), radius of gyration (Rg), number of hydrogen bonds between ligand and protein during the time of simulation, and root mean square fluctuations (RMSF) of protein and ligands were calculated, and components of binding free energy were calculated using the molecular mechanic/Poisson-Boltzmann surface area (MM/PBSA) method. The result of all the analysis indicated that ZINC61991204 and ZINC67910260 are drug-like and nontoxic and have a high potential for inhibiting Mpro.

Giloy: a potential anti-COVID-19 herb with propitious pharmacological attributes: a short review.

Plant-based medicine actually restores the balance in the body instead of treating the source of the disease. The strain of coronavirus (SAR-CoV-2) going to be more serious due to the lack of a reliable treatment option. Holistic treatment for this disease is in the form of Ayurveda as traditional medicine. As the infection of coronavirus is spreading like a wildfire, so the one way to fight is 'immunity'. Building immunity is the only way to stay safe and healthy and prepared themselves for the ongoing pandemic. In the current scenario, good immunity safeguard us from disease progression and prevention from this deadly virus. Giloy herb came into the limelight after the start of the COVID-19 pandemic due to its immunomodulatory and antiviral activity. The genome sequencing of Giloy is proved to be a breakthrough for controlling the COVID-19.Communicated by Ramaswamy H. Sarma.

Potential inhibitors of SARS-CoV-2 (COVID 19) proteases PLpro and Mpro/ 3CLpro: molecular docking and simulation studies of three pertinent medicinal plant natural components.

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - coronavirus disease 2019 (COVID-19) has raised a severe global public health issue and creates a pandemic situation. The present work aims to study the molecular -docking and dynamic of three pertinent medicinal plants i.e. Eurycoma harmandiana, Sophora flavescens and Andrographis paniculata phyto-compounds against SARS-COV-2 papain-like protease (PLpro) and main protease (Mpro)/3-chymotrypsin-like protease (3CLpro). The interaction of protein targets and ligands was performed through AutoDock-Vina visualized using PyMOL and BIOVIA-Discovery Studio 2020. Molecular docking with canthin-6-one 9-O-beta-glucopyranoside showed highest binding affinity and less binding energy with both PLpro and Mpro/3CLpro proteases and was subjected to molecular dynamic (MD) simulations for a period of 100ns. Stability of the protein-ligand complexes was evaluated by different analyses. The binding free energy calculated using MM-PBSA and the results showed that the molecule must have stable interactions with the protein binding site. ADMET analysis of the compounds suggested that it is having drug-like properties like high gastrointestinal (GI) absorption, no blood-brain barrier permeability and high lipophilicity. The outcome revealed that canthin-6-one 9-O-beta-glucopyranoside can be used as a potential natural drug against COVID-19 protease.