Since its first report in December 2019 from China, the COVID-19 pandemic caused by the beta-coronavirus SARS-CoV-2 has spread at an alarming pace infecting about 5.59 million, and claiming the lives of more than 0.35 million individuals across the globe. The lack of a clinically approved vaccine or drug remains the biggest bottleneck in combating the pandemic. Drug repurposing can expedite the process of drug development by identifying known drugs which are effective against SARS-CoV-2. The SARS-CoV-2 main protease is a promising drug target due to its indispensable role in viral multiplication inside the host. In the present study an E-pharmacophore hypothesis was generated using a crystal structure of the viral protease in complex with an imidazole carbaximide inhibitor. Drugs available in the superDRUG2 database were used to identify candidate drugs for repurposing. The hits obtained from the pharmacophore based screening were further screened using a structure based approach involving molecular docking at different precisions. The binding energies of the most promising compounds were estimated using MM-GBSA. The stability of the interactions between the selected drugs and the target were further explored using molecular dynamics simulation at 100 ns. The results showed that the drugs Binifibrate and Bamifylline bind strongly to the enzyme active site and hence they can be repurposed against SARS-CoV-2. However, U.S Food and Drug Administration have withdrawn Binifibrate from the market as it was having some adverse health effects on patients.
Background
The nasal carriage of SARS-CoV-2 has been reported as the key factor transmitting COVID-19. Interventions that can reduce viral shedding from the nasopharynx could potentially mitigate the severity of the disease and its contagiousness. Herbal formulation of Citrus medica and Zingiber officinale is recommended in an Ayurvedic text as a nasal rinse in the management of contagious fevers. These herbs are also indicated in the management of respiratory illnesses and have been attributed with activity against pathogenic organisms in other texts. Molecular docking studies of the phytocompounds of C. medica and Z. officinale were done to find out whether these compounds could inhibit the receptor binding of SARS-CoV-2 spike protein (S protein) as well as the angiotensin-converting enzyme 2 (ACE-2), as evidenced from their docking into binding/active sites.
Results
The proteins of SARS-CoV-2, essential for its entry into human cells and highly expressed in the goblet and ciliated cells of nasal epithelium, play a significant role in contagiousness of the virus. Docking studies indicated that the specific compounds present in C. medica and Z. officinale have significant affinity in silico to spike protein of virus and ACE-2 receptor in the host.
Conclusion
In silico studies suggest that the phytochemical compounds in C. medica and Z. officinale may have good potential in reducing viral load and shedding of SARS-CoV-2 in the nasal passages. Further studies are recommended to test its efficacy in humans for mitigating the transmission of COVID-19.
The world has come to a sudden halt due to the incessant spread of a viral pneumonia dubbed COVID-19 caused by the beta-coronavirus, SARS-CoV-2. The main protease of SARS-CoV-2 plays a key role in the replication and propagation of the virus in the host cells. Inhibiting the protease blocks the replication of the virus; therefore it is considered as an attractive therapeutic target. Here we describe the screening of the DrugBank database, a public repository for small molecule therapeutics, to identify approved or experimental phase drugs that can be repurposed against the main protease of SARS-CoV-2. The initial screening was performed on more than 13,000 drug entries in the target database using an energy optimised pharmacophore hypothesis AARRR. A subset of the molecules selected based on the fitness score was further screened using molecular docking by sequentially filtering the molecules through the high throughput virtual screening, extra precision and standard precision docking modalities. The best hits were subjected to binding free energy estimation using the MM-GBSA method. Approved drugs viz, Cobicistat, Larotrectinib and Simeprevir were identified as potential candidates for repurposing. Drugs in the discovery phase identified as inhibitors include the known cysteine protease inhibitors, Calpain inhibitor IV and an experimental cathepsin F inhibitor. In order to analyse the stability of the binding interactions, the known cysteine protease inhibitors viz, Simeprevir, calpain inhibitor IV and the cathepsin F inhibitor in complex M pro were subjected to molecular dynamics simulations at 100 ns. Based on the results Simeprevir was found to be a strong inhibitor of SARS-CoV-2 M pro .
The world has come to a sudden halt due to the incessant spread of a viral pneumonia dubbed
COVID-19 caused by the beta-coronavirus, SARS-CoV-2. The pandemic spread of the virus
has already claimed lakhs of valuable lives and has infected millions of people across the globe.
The situation is further worsened by the fact that there is no approved therapeutics currently
available for the treatment of the disease. The only way to handle the crisis is the rapid
development of a therapeutic strategy to combat the virus. Computational biology offers
resources to rapidly identify novel drug leads and to repurpose existing drugs at the expense of
minimal resources and time. The main protease of SARS-CoV-2 is key to the replication and
propogation of the virus in the host cells. Inhibiting the protease blocks replication and hence
is an attractive therapeutic target in the virus. The crystal structures of the protein in complex
with inhibitors are available in public databases. Here we describe the screening of the
DrugBank database, a public repository for small molecule therapeutics, to identify approved
or experimental phase drugs that can be repurposed against the main protease of SARS-CoV2. The initial screening was performed on more than 13,000 drug entries in the target database
using an energy optimised pharmacophore hypothesis AARRR. A sub-set of the molecules
selected based on the fitness score was further screened using molecular docking by
sequentially filtering the molecules through the high throughput virtual screening, extra
precision and standard precision docking modalities. The most promising hits were subjected
to binding free energy estimation using the MMGBSA method. Approved drugs viz, Cobicistat,
Larotrectinib and Simeprevir were identified as potential candidates for repurposing. Drugs in
the discovery phase identified as inhibitors include the known cysteine protease inhibitors,
Calpain inhibitor IV and an experimental cathepsin F inhibitor.
<p>The
total cases of novel corona virus (SARS-CoV-2)
infections is more than one million and total deaths recorded is more than fifty thousand.
The research for developing vaccines and drugs against SARS-CoV-2 is going on in different parts of the world. Aim
of the present study was
to identify
potential drug
candidates against
SARS-CoV-2 from existing drugs using <i>in silico</i> molecular modeling and
docking. The targets for the present study was the spike
protein and the main
protease of SARS-CoV-2. The study was able to identify some drugs that can either bind to the spike protein receptor
binding domain or the main protease of SARS-CoV-2. These include some of the antiviral drugs. These
drugs might have the potential
to inhibit the infection and viral replication.</p>
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