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High Throughput Virtual Screening to Discover Inhibitors of the Main Protease of the Coronavirus SARS-CoV-2
Article

In Silico Identification of Potential Natural Product Inhibitors of Human Proteases Key to SARS-CoV-2 Infection

1
The Institute of Mathematical Sciences (IMSc), Chennai 600113, India
2
Homi Bhabha National Institute (HBNI), Mumbai 400094, India
3
School of Chemical Sciences, National Institute of Science Education and Research (NISER), Bhubaneswar 752050, India
*
Authors to whom correspondence should be addressed.
Lead Contact.
Academic Editor: Antonio Carta
Molecules 2020, 25(17), 3822; https://doi.org/10.3390/molecules25173822
Received: 27 July 2020 / Revised: 15 August 2020 / Accepted: 16 August 2020 / Published: 22 August 2020
(This article belongs to the Special Issue Antiviral Agents)
Presently, there are no approved drugs or vaccines to treat COVID-19, which has spread to over 200 countries and at the time of writing was responsible for over 650,000 deaths worldwide. Recent studies have shown that two human proteases, TMPRSS2 and cathepsin L, play a key role in host cell entry of SARS-CoV-2. Importantly, inhibitors of these proteases were shown to block SARS-CoV-2 infection. Here, we perform virtual screening of 14,011 phytochemicals produced by Indian medicinal plants to identify natural product inhibitors of TMPRSS2 and cathepsin L. AutoDock Vina was used to perform molecular docking of phytochemicals against TMPRSS2 and cathepsin L. Potential phytochemical inhibitors were filtered by comparing their docked binding energies with those of known inhibitors of TMPRSS2 and cathepsin L. Further, the ligand binding site residues and non-covalent interactions between protein and ligand were used as an additional filter to identify phytochemical inhibitors that either bind to or form interactions with residues important for the specificity of the target proteases. This led to the identification of 96 inhibitors of TMPRSS2 and 9 inhibitors of cathepsin L among phytochemicals of Indian medicinal plants. Further, we have performed molecular dynamics (MD) simulations to analyze the stability of the protein-ligand complexes for the three top inhibitors of TMPRSS2 namely, qingdainone, edgeworoside C and adlumidine, and of cathepsin L namely, ararobinol, (+)-oxoturkiyenine and 3α,17α-cinchophylline. Interestingly, several herbal sources of identified phytochemical inhibitors have antiviral or anti-inflammatory use in traditional medicine. Further in vitro and in vivo testing is needed before clinical trials of the promising phytochemical inhibitors identified here. View Full-Text
Keywords: COVID-19; TMPRSS2; cathepsin L; molecular docking; molecular dynamics; non-covalent interactions; phytochemical inhibitors COVID-19; TMPRSS2; cathepsin L; molecular docking; molecular dynamics; non-covalent interactions; phytochemical inhibitors
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MDPI and ACS Style

Vivek-Ananth, R.P.; Rana, A.; Rajan, N.; Biswal, H.S.; Samal, A. In Silico Identification of Potential Natural Product Inhibitors of Human Proteases Key to SARS-CoV-2 Infection. Molecules 2020, 25, 3822. https://doi.org/10.3390/molecules25173822

AMA Style

Vivek-Ananth RP, Rana A, Rajan N, Biswal HS, Samal A. In Silico Identification of Potential Natural Product Inhibitors of Human Proteases Key to SARS-CoV-2 Infection. Molecules. 2020; 25(17):3822. https://doi.org/10.3390/molecules25173822

Chicago/Turabian Style

Vivek-Ananth, R.P., Abhijit Rana, Nithin Rajan, Himansu S. Biswal, and Areejit Samal. 2020. "In Silico Identification of Potential Natural Product Inhibitors of Human Proteases Key to SARS-CoV-2 Infection" Molecules 25, no. 17: 3822. https://doi.org/10.3390/molecules25173822

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