Identification of FDA-approved drugs against SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) through computational virtual screening.

The SARS-CoV-2 coronavirus is responsible for the COVID-19 outbreak, which overwhelmed millions of people worldwide; hence, there is an urgency to identify appropriate antiviral drugs. This study focuses on screening compounds that inhibit RNA-dependent RNA-polymerase (RdRp) essential for RNA synthesis required for replication of positive-strand RNA viruses. Computational screening against RdRp using Food and Drug Administration (FDA)-approved drugs identified ten prominent compounds with binding energies of more than - 10.00 kcal/mol, each a potential inhibitor of RdRp. These compounds' binding energy is comparable to known RdRp inhibitors remdesivir (IC50 = 10.09 µM, SI = 4.96) and molnupiravir (EC50 = 0.67 - 2.66 µM) and 0.32-2.03 µM). Remdesivir and molnupiravir have been tested in clinical trial and remain authorized for emergency use in the treatment of COVID-19. In docking simulations, selected compounds are bound to the substrate-binding pocket of RdRp and showed hydrophobic and hydrogen bond interaction. For molecular dynamics simulation, capmatinib, pralsetinib, ponatinib, and tedizolid phosphate were selected from the initial ten candidate compounds. MD simulation indicated that these compounds are stable at 50-ns MD simulation when bound to RdRp protein. The screen hit compounds, remdesivir, molnupiravir, and GS-441524, are bound in the substrate binding pocket with good binding-free energy. As a consequence, capmatinib, pralsetinib, ponatinib, and tedizolid phosphate are potential new inhibitors of RdRp protein with potential of limiting COVID-19 infection by blocking RNA synthesis. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02072-1.

In silico screening of FDA approved drugs against ACE2 receptor: potential therapeutics to inhibit the entry of SARS-CoV-2 to human cells.

An unknown coronavirus that emerged sometime at the end of 2019 in China, the novel SARS-CoV-2, now called COVID-19, has spread all over the world. Several efforts have been made to prevent or treat this disease, though not with success. The initiation of COVID-19 viral infection involves specific binding of SARS-CoV-2 to the host surface of the receptor, ACE2. The ACE2- SARS-CoV-2 complex then gets transferred into the endosomes where the endosomal acidic proteases cleave the S protein present in SARS-CoV-2, activating its fusion and release of the viral genome. We have carried out detailed and thorough in silico studies to repurpose FDA approved compounds to inhibit human ACE2 receptor so as to prevent the viral entry. Our study reveals that five compounds show good binding to the ACE2 receptor and hence are potential candidates to interact with ACE2 and prevent it's recognition by the virus, SARS-CoV-2. Communicated by Ramaswamy H. Sarma.

Identification of FDA-approved drugs against SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) through computational virtual screening

The SARS-CoV-2 coronavirus is responsible for the COVID-19 outbreak, which overwhelmed millions of people worldwide;hence, there is an urgency to identify appropriate antiviral drugs. This study focuses on screening compounds that inhibit RNA-dependent RNA-polymerase (RdRp) essential for RNA synthesis required for replication of positive-strand RNA viruses. Computational screening against RdRp using Food and Drug Administration (FDA)-approved drugs identified ten prominent compounds with binding energies of more than − 10.00 kcal/mol, each a potential inhibitor of RdRp. These compounds’ binding energy is comparable to known RdRp inhibitors remdesivir (IC50 = 10.09 μM, SI = 4.96) and molnupiravir (EC50 = 0.67 − 2.66 µM) and 0.32–2.03 µM). Remdesivir and molnupiravir have been tested in clinical trial and remain authorized for emergency use in the treatment of COVID-19. In docking simulations, selected compounds are bound to the substrate-binding pocket of RdRp and showed hydrophobic and hydrogen bond interaction. For molecular dynamics simulation, capmatinib, pralsetinib, ponatinib, and tedizolid phosphate were selected from the initial ten candidate compounds. MD simulation indicated that these compounds are stable at 50-ns MD simulation when bound to RdRp protein. The screen hit compounds, remdesivir, molnupiravir, and GS-441524, are bound in the substrate binding pocket with good binding-free energy. As a consequence, capmatinib, pralsetinib, ponatinib, and tedizolid phosphate are potential new inhibitors of RdRp protein with potential of limiting COVID-19 infection by blocking RNA synthesis. Supplementary Information The online version contains supplementary material available at 10.1007/s11224-022-02072-1.

Virtual high throughput screening: Potential inhibitors for SARS-CoV-2 PLPRO and 3CLPRO proteases.

The pandemic, COVID-19, has spread worldwide and affected millions of people. There is an urgent need, therefore, to find a proper treatment for the novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the causative agent. This paper focuses on identifying inhibitors that target SARS-CoV-2 proteases, PLPRO and 3CLPRO, which control the duplication and manages the life cycle of SARS-CoV-2. We have carried out detailed in silico Virtual high-throughput screening using Food and Drug Administration (FDA) approved drugs from the Zinc database, COVID-19 clinical trial compounds from Pubchem database, Natural compounds from Natural Product Activity and Species Source (NPASS) database and Maybridge database against PLPRO and 3CLPRO proteases. After thoroughly analyzing the screening results, we found five compounds, Bemcentinib, Pacritinib, Ergotamine, MFCD00832476, and MFCD02180753 inhibit PLPRO and six compounds, Bemcentinib, Clofazimine, Abivertinib, Dasabuvir, MFCD00832476, Leuconicine F inhibit the 3CLPRO. These compounds are stable within the protease proteins' active sites at 20ns MD simulation. The stability is revealed by hydrogen bond formations, hydrophobic interactions, and salt bridge interactions. Our study results also reveal that the selected five compounds against PLPRO and the six compounds against 3CLPRO bind to their active sites with good binding free energy. These compounds that inhibit the activity of PLPRO and 3CLPRO may, therefore, be used for treating COVID-19 infection.

In-silico screening for identification of potential inhibitors against SARS-CoV-2 transmembrane serine protease 2 (TMPRSS2).

A new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a respiratory infection out broke in December 2019 in Wuhan, Hubei province, China, resulted in pandemic conditions worldwide. COVID-19 spread swiftly around the world over with an alert of an emergency for an adequate drug. Therefore, in this research, we repurposed the FDA-approved medicines to find the prominent drug used to cure the COVID infected patients. We performed homology modeling of the transmembrane serine protease 2 (TMPRSS2), responsible for the viral entry. The prediction of the transmembrane region and the Conserved Domain in TMPRSS2 protein was made for docking. 4182 FDA-approved compounds from the ZINC database were downloaded and used for the calculation of physicochemical properties. Two thousand eight hundred fifteen screened compounds were used for molecular docking against the modelled protein structure. From which top hit compounds based on binding energy were extracted. At 1st site pose, ZINC3830554 showed the highest binding energy -12.91kcal/mol by forming Salt Bridge at LYS143, Hydrogen bond at ALA8, VAL45, HIS47, SER142, ASN277, ASN359, and TRP363. The hydrophobic Interactions at PHE3, LEU4, ALA7, ALA8, ALA139, PRO197, and PHE266. In the 2nd site pose, ZINC203686879 shows the highest binding energy (-12.56 kcal/mol) and forms a hydrophobic interaction with VAL187, VAL189, HIS205, LYS301, GLN347, TRP370 and hydrogen bond was at GLY300, THR302, GLN347, SER350 residues. These hit compounds were subjected to stability checks between the protein-ligand complex through the dynamics simulation (MD), and binding free energy was calculated through the Molecular Mechanics energies combined with Poisson-Boltzmann (MM/PBSA) method. We hope that hit compounds would be an efficient inhibitor that can block the TMPRSS2 activity and resist the entry of the SARS-CoV-2 virus into targeted human cells by reducing the virus's infectivity and transmissibility.