Phytochemicals-Traditional Chinese Medicine (TCM): Scientist from the Tianjin Medical University Cancer Institute & Hospital -China, the Central South University,Hunan-China and the HuaZhong Agricultural University,Wuhan-China have in a new silico computational molecular docking study found that the phytochemicals quercetin, puerarin and kaempferol frequently found in most relevant Traditional Chinese Medicines to treat respiratory diseases and viral infections could inhibit the SARS-CoV-2 coronavirus.
COVID-19 that is fast wreaking havoc around the world and claiming thousands of lives each day has raised an urgent need for therapeutics to contain the ever growing deadly pandemic.
To date however no effective treatment has been found for SARS-CoV-2 infection. Here the study team puerarin, quercetin and kaempferol as potential compounds with binding activity to ACE2 by using Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP).
Detailed molecular docking analysis showed that puerarin and quercetin exhibit good binding affinity to ACE2, which was validated by surface plasmon resonance (SPR) assay.
In addition, SPR-based competition assay revealed that puerarin and quercetin could significantly affect the binding of viral S-protein to ACE2 receptor.
Importantly, quercetin could also bind to the RBD domain of S-protein, suggesting not only a receptor blocking, but also a virus neutralizing effect of quercetin on SARS-CoV-2.
The study results from network pharmacology and bioinformatics analysis support a view that quercetin is involved in host immunomodulation, which further renders it a promising candidate against COVID-19. Moreover, given that puerarin is already an existing food supplement, results from this study not only provide insight into its action mechanism, but also propose a prompt application of it on COVID-19 patients for assessing its clinical feasibility.
The study results were published in the peer reviewed Computational and Structural Biotechnology Journal. https://www.sciencedirect.com/science/article/pii/S2001037020304773?via%3Dihub
In the study, of the three compounds, quercetin showed the highest binding affinity to both the ACE2 receptor and the receptor-binding domain of the SARS-CoV-2 spike protein, and could thus provide a dual synergistic effect.
Thailand Medical News had already done a feature article on the merits of using quercetin as an adjuvant to treat COVID-19 since August this year.
The SARS-CoV-2, the causative pathogen of the COVID-19 pandemic, infects human hosts by binding with the human angiotensin-converting enzyme 2 (ACE2) receptor on their cells, notably the epithelium lining the respiratory tract. The receptor-binding domain (RBD) of the coronavirus spike protein binds to ACE2 followed by membrane fusion to the host cell, thus allowing the virus to infiltrate the cell and commence replication.
TCM or Traditional Chinese medicine, widely used for many diseases, showed therapeutic effects during the 2003 SARS-CoV epidemic. The RBD of the SARS-CoV-2 has significant structural homology with SARS-CoV. Although the use of Chinese herbs with modern medicine has shown benefits in COVID-19 patients, several components are present in the herbs and have complex interactions, making it challenging to uncover the molecular mechanisms responsible for its therapeutic effects.
Numerous computational studies have helped predict active compounds in the medicinal herbs with the potential to accelerate traditional medicine-based drug discovery.
The study team from China used computational analysis to discover potential molecule candidates against SARS-CoV-2 infection. Utilizing the Traditional Chinese Medicine Pharmacology database, they screened for molecules that could target ACE2.
The study team identified the compound puerarin that could target ACE2. Subsequently they screened for Chinese herbs that have this compound in the database and found five. Furthermore, since it is thought that compounds in the same herbal medicine have synergistic properties, they expanded their search to include all the compounds in the five herbs to arrive at 41 compounds.
However upon analyzing which compounds were present in the maximum number of herbs, they found puerarin was present in all the five herbs, and quercetin and kaempferol were present in three herbs.
The study team then predicted potential drug targets of the selected compounds using the database, leading to 240 possible targets. Upon further analysis, they selected puerarin, quercetin, and kaempferol for further study.
The team next performed molecular docking analysis to determine potential binding sites and binding affinity to ACE2. All the three compounds could bind on the same region of ACE2, which is located some distance from the binding position of SARS-CoV-2. It is likely the compounds are causing changes in conformations rather than competing with the spike protein to bind to ACE2. Quercetin had the highest binding affinity, forming both strong and weak hydrogen bonds.
The researchers also experimentally determined the binding of the three compounds to ACE2 using surface plasmon resonance. Similar to the theoretical analysis, they found quercetin had higher binding affinity to ACE2 than puerarin. They also observed that puerarin affected the binding of spike protein to ACE2, and quercetin almost completely disrupted the spike protein binding to ACE2. Molecular docking analysis showed that quercetin has high binding affinity to the spike protein. Using pathway enrichment analysis for the COVID-19-related genes, they found quercetin affected the immune-modulation and viral infection activities.
Interestingly, all the three compounds tested were found in the herb Radix Bupleuri confirming that compounds in a single herb have synergistic pharmacological properties. The herb is popular in China and has been used to treat flu, inflammation, malaria, and hepatitis B.
A recent study showed that Radix Bupleuri was among the 26 selected Chinese herbal medicines or CHMs with great potential to directly inhibit SARS-CoV-2 infection, and was advised to use at the early course of infection by senior TCM practitioners. https://www.sciencedirect.com/science/article/pii/S2095496420300157
The phytochemical Puerarin has been approved for use in China for decades and could be an ideal drug repurposed for its antiviral properties. Although its binding affinity is lower than quercetin, it has a safe dose limit of about 0.5 gram, so it could be used at a high dose to achieve a suitable antiviral effect. It also has beneficial effects on fever, cardiovascular disease, and neurological dysfunction. https://onlinelibrary.wiley.com/doi/abs/10.1002/ptr.5083
Puerarin can be co-administrated as a adjuvant to help improve the symptoms and prognosis of COVID-19 patients. In this context, the “old drug new use” of puerarin on COVID-19 can minimize the translational gap between drug development and clinical outcomes, providing an optimal outlet for timely developing effective therapeutics against the emerging pandemics.
The phytochemical Quercetin showed a higher binding affinity to both ACE2 and the RBD of the spike protein. The dual binding effect of quercetin could therefore be synergistic and provide a strong antiviral effect against SARS-CoV-2.
Notably, according to the recently resolved cryo-EM structure of full-length ACE2-RBD-B0AT1 complex, the interaction between ACE2 and the virus is to a great extend dependent on the residues Tyr453 and Gln474 of RBD, which are only several residues away from the quercetin binding pocket on RBD. These results support the view that the conformational change of these RBD residues upon the binding of quercetin plays an important role in the disrupted binding of S-protein to ACE2. Thus, quercetin impairs the interaction between S-protein and ACE2 through simultaneous binding with both of them, and this dual-targeting approach may generate a synergistic disruptive effect, and therefore result in a better anti-SARS-CoV-2 activity. https://www.nature.com/articles/s41586-020-2180-5
Furthermore, since analysis suggested that quercetin could affect immunomodulation, and because studies have shown patients with severe COVID-19 disease tend to experience cytokine storms, quercetin could help alleviate symptoms in such cases.
These are among more emerging studies that show the potential to use herbs and phytochemicals to treat COVID-19.
Thailand Medical News has been working on such initiatives since February this year staring with a focus on the licorice root initially and subsequently into a variety of herbs and phytochemicals. https://www.thailandmedical.news/news/new-therapeutic-teas-
Despite making a headway into herbal research to treat COVID-19 and even Long COVID, we are unfortunately unable to secure help or funding to further our studies and production as we based in a ‘garbage country’ where greed, nepotism, egoism and corruption is at play along with sheer ignorance and stupidity. Also we do not get any support from any of our readers etc. To date we only received help for our herbal project from a single generous and kind local individual.
Let’s hope that the COVID-19 exists for a long time with waves of increasing destruction and intensity with more people getting infected and dying, then perhaps people would wake up and start supporting herb related causes.
For more on Phytochemicals-Traditional Chinese Medicine (TCM), keep on logging to Thailand Medical News.
Source: Thailand Medical News