Screening of active ingredients from traditional Chinese medicine against the novel Coronavirus based on molecular docking

ADMEN prediction was used to perform the first round screening from Traditional Chinese Medicine Database and Analysis Platform(TCMSP). then VASARA and molecular docking were used to screen again based on targets spike glyoprotein and angiotensin converting enzyme 2. and finally the interaction between target and drug was analyzed. 425 candidate ingredients of traditional Chinese medicine were screened from TCMSP database. when targeted by Spike glycoprotein. 12 ingredients were screened. They were contained artemisia apiacea salvia miltiorrhiza bge. scutellaria baicalensis. pinellia ternate. liquorice. radixImplettri and other traditional Chinese medicine. With ACE2 as the target. 77 components of traditional Chinese medicine were screened out. including salvia miltiorrhiza bge scutellaria baicalensis. pinellia ternatc. Liquorice. radix bupleuri. ephedra and other traditional Chinese medicine. At last. salviolone and dihydrotanshinlactone were found to be the potential inhibitor.

Computational study of kaurene diterpenoids for antivirals against SARS-CoV-2

Kaurene diterpenoids were found in some plants such as Adenostemma lavenia and Pteris semipinnata to have antioxidant, antiinflammatory, anticancer, antitumor, cytotoxic, and antiviral activities. To evaluate the potency of kaurene diterpenoids as antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we conducted an in silico study of several kaurene diterpenoids and antiviral drugs such as remdesivir and favipiravir in inhibition essential SARS-CoV-2 proteins including 3CLpro, Plpro, nucleocapsid (N), and membrane (M) through molecular docking, molecular dynamic (MD) simulations, adsorption, distribution, metabolism, excretion, and toxicity (ADMET), and pharmacokinetic properties prediction using a number of pieces of software. The docking study showed that the kaurene diterpene glycosides have a higher binding affinity to the 3CLpro, N, and M proteins of SARS-CoV-2 than other kaurene diterpenoids and even antiviral drugs such as remdesivir and favipiravir. Inhibition of these nonstructural and structural proteins has a significant impact on disrupting the viral replication and viral assembly of SARS-CoV-2. Almost all the complexes showed minimum deviation and fluctuation, indicating that each ligand is strongly bound to the binding site of proteins. ADMET prediction revealed all kaurene diterpenoids were well absorbed by the human intestine, noncarcinogenic, and did not cause mutations in DNA. Therefore, we expected these materials could be a potential preventive and therapeutic agent in the fight against the COVID-19 disease. © 2022. Nurlela Nurlela et al. This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License

Andrographolide and Deoxyandrographolide Inhibit Protease and IFN-Antagonist Activities of Foot-and-Mouth Disease Virus 3Cpro.

Foot-and mouth-disease (FMD) caused by the FMD virus (FMDV) is highly contagious and negatively affects livestock worldwide. The control of the disease requires a combination of measures, including vaccination; however, there is no specific treatment available. Several studies have shown that plant-derived products with antiviral properties were effective on viral diseases. Herein, antiviral activities of andrographolide (AGL), deoxyandrographolide (DAG), and neoandrographolide (NEO) against FMDV serotype A were investigated using an in vitro cell-based assay. The results showed that AGL and DAG inhibited FMDV in BHK-21 cells. The inhibitory effects of AGL and DAG were evaluated by RT-qPCR and exhibited EC50 values of 52.18 ± 0.01 µM (SI = 2.23) and 36.47 ± 0.07 µM (SI = 9.22), respectively. The intracellular protease assay revealed that AGL and DAG inhibited FMDV 3Cpro with IC50 of 67.43 ± 0.81 and 25.58 ± 1.41 µM, respectively. Additionally, AGL and DAG significantly interfered with interferon (IFN) antagonist activity of the 3Cpro by derepressing interferon-stimulating gene (ISGs) expression. The molecular docking confirmed that the andrographolides preferentially interacted with the 3Cpro active site. However, NEO had no antiviral effect in any of the assays. Conclusively, AGL and DAG inhibited FMDV serotype A by interacting with the 3Cpro and hindered its protease and IFN antagonist activities.

In silico molecular docking and molecular dynamics examination of Andrographis paniculata compounds of andrographolide, neoandrographolide, and 5-hydroxy-7,8,2',3'-tetramethoxyflavone inhibition activity to SARS-CoV-2 main protease

In this work, Andrographis paniculata compounds of Andrographolide, Neoandrographolide, and 5-hydroxy-7,8,2',3'-tetramethoxyflavone inhibition activity to SARS CoV-2 main protease were examined through in silico molecular docking and molecular dynamics simulation, with Remdesivir as control ligand. Docking score and MMGBSA were examined as well as molecular dynamics parameters: RMSD, RMSF and Protein ligand contact fraction. Our study found that Andrographis paniculata compounds of Andrographolide, Neoandrographolide, and 5-hydroxy-7,8,2',3'-tetramethoxyflavone have comparable inhibition activity to SARS CoV-2 main protease in comparison to Remdesivir. 5-hydroxy7,8,2',3'-tetramethoxyflavone has the lowest docking score, which was further validated by protein ligand contact fraction examination, although MMGBSA score is lowest for Remdesivir.

In silico identification of potential inhibitors against main protease of SARS-CoV-2 6LU7 from Andrographis panniculata via molecular docking, binding energy calculations and molecular dynamics simulation studies.

BACKGROUND: The ongoing global outbreak of new corona virus (SARS-CoV-2) has been recognized as global public health concern since it causes high morbidity and mortality every day. Due to the rapid spreading and re-emerging, we need to find a potent drug against SARS-CoV-2. Synthetic drugs, such as hydroxychloroquine, remdisivir have paid more attention and the effects of these drugs are still under investigation, due to their severe side effects. Therefore, the aim of the present study was performed to identify the potential inhibitor against main protease SARS-CoV-2 6LU7. OBJECTIVE: In this study, RO5, ADME properties, molecular dynamic simulations and free binding energy prediction were mainly investigated. RESULTS: The molecular docking study findings revealed that andrographolide had higher binding affinity among the selected natural diterpenoids compared to co-crystal native ligand inhibitor N3. The persistent inhibition of Ki for diterpenoids was analogous. Furthermore, the simulations of molecular dynamics and free binding energy findings have shown that andrographolide possesses a large amount of dynamic properties such as stability, flexibility and binding energy. CONCLUSION: In conclusion, findings of the current study suggest that selected diterpenoids were predicted to be the significant phytonutrient-based inhibitor against SARS-CoV-2 6LU7 (Mpro). However, preclinical and clinical trials are needed for the further scientific validation before use.

Computer aided identification of potential SARS CoV-2 main protease inhibitors from diterpenoids and biflavonoids of Torreya nucifera leaves.

SARS CoV-2 is the causative agent of the pandemic disease COVID-19. There is an urgent need for effective drugs or vaccines which can effectively combat this outbreak. The main protease (Mpro), a key component for the SARS CoV-2 replication, is considered to be one of the important drug targets for developing anti-COVID-19 drugs. This SARS CoV-2 Mpro/cysteine protease has high sequence similarity with the same protease from SARS CoV-1. Previously, it has been shown experimentally that eight diterpenoids and four biflavonoids derived from the leaf of Torreya nucifera show inhibitory effect on the cleavage/catalytic activity of the SARS CoV-1 Mpro. But whether these phytochemicals exhibit any inhibitory effect on SARS CoV-2 Mpro is unclear. To understand this fact, here, we have adopted various in-silico approaches. Diterpenoids and biflavonoids those qualified pharmacological test (hinokiol, amentoflavone, bilobetin and ginkgetin) and two well-known Mpro inhibitors (N3 and lopinavir) were subjected for molecular docking studies. Only three biflavonoids (amentoflavone, bilobetin and ginkgetin) were selected by comparing their binding affinities with N3 and lopinavir. They interacted with two most important catalytic residues of Mpro (His41 and Cys145). Molecular dynamics studies further revealed that these three Mpro-biflavonoid complexes are highly stable and share a similar degree of compactness. Besides, these complexes experience less conformational fluctuations and more expansion than Mpro-N3 and/or Mpro-lopinavir complex. MM-GBSA and H-bond analysis further corroborated these findings. Altogether, our study suggested that these three biflavonoids could possibly inhibit the proteolytic/catalytic activity of SARS CoV-2 Mpro and might be useful for COVID-19 treatment.Communicated by Ramaswamy H. Sarma.