Abstract
Since 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been rapidly spreading worldwide, causing hundreds of millions of infections. Despite the development of vaccines, insufficient protection remains a concern. Therefore, the screening of drugs for the treatment of coronavirus disease 2019 (COVID-19) is reasonable and necessary. This study utilized bioinformatics for the selection of compounds approved by the U.S. Food and Drug Administration with therapeutic potential in this setting. In addition, the inhibitory effect of these compounds on the enzyme activity of transmembrane protease serine 2 (TMPRSS2), papain-like protease (PLpro), and 3C-like protease (3CLpro) was evaluated. Furthermore, the capability of compounds to attach to the spike-receptor-binding domain (RBD) was considered an important factor in the present assessment. Finally, the antiviral potency of compounds was validated using a plaque reduction assay. Our funnel strategy revealed that tamoxifen possesses an anti-SARS-CoV-2 property owing to its inhibitory performance in multiple assays. The proposed time-saving and feasible strategy may accelerate drug screening for COVID-19 and other diseases.
Highlights
At the end of 2019, a novel disease that causes severe acute respiratory syndrome (SARS), termed coronavirus disease 2019 (COVID-19), spread in Wuhan, China [1]
We observed that doxorubicin interacts with Arg182, Asn192, Asn193, Thr287, and Trp290 of transmembrane protease serine 2 (TMPRSS2) with hydrogen bonds (Figure 2a), while niclosamide interacts with Ile381, Gly383, Thr387, Asp435, and Asp440 of TMPRSS2 through hydrogen bonding (Figure 2c)
For TMPRSS2 docking, we found that doxorubicin interacts with Arg182, Asn192, Asn193, Thr287, and Trp290, while niclosamide interacts with Ile381, Gly383, Thr387, Asp435, and Asp440
Summary
At the end of 2019, a novel disease that causes severe acute respiratory syndrome (SARS), termed coronavirus disease 2019 (COVID-19), spread in Wuhan, China [1]. Until 15 October 2021, there were 240 million confirmed cases and 4.9 million deaths reported worldwide (https://www.who.int/, accessed on 15 October 2021). SARScoronavirus 2 (SARS-CoV-2) is the pathogen responsible for COVID-19. It belongs to Pharmaceutics 2022, 14, 176. During the initiation of infection, the receptor-binding domain (RBD) of the spike protein binds to host membrane-associated angiotensin-converting enzyme 2 (ACE2), and transmembrane protease serine 2 (TMPRSS2) proteolytically cleaves and activates viral envelope glycoproteins [4]. The interaction of a spike with ACE2 promotes the fusion of the virus and the host cell membrane [5]. In addition to SARS-CoV-2, other types of coronaviruses and influenza viruses rely on TMPRSS2 for entry into host cells [6,7]
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