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Open AccessFeature PaperArticle

Virtual Screening of Natural Products against Type II Transmembrane Serine Protease (TMPRSS2), the Priming Agent of Coronavirus 2 (SARS-CoV-2)

H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
Jamil-ur-Rahman Center for Genome Research, PCMD, ICCBS, University of Karachi, Karachi 75270, Pakistan
NUTRIKETO_LAB Unisa-“San Giuseppe Moscati” National Hospital (AORN), Contrada Amoretta, 83100 Avellino (AV), Italy
Dipartimento di Farmacia, University of Salerno. Via Giovanni Paolo II, 84084 Fisciano (SA), Italy
Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan
Authors to whom correspondence should be addressed.
Academic Editors: Karel Šmejkal and Derek J. McPhee
Molecules 2020, 25(10), 2271;
Received: 16 April 2020 / Revised: 27 April 2020 / Accepted: 10 May 2020 / Published: 12 May 2020
(This article belongs to the Special Issue Bioactive Natural Compounds and Their Mechanisms of Action)
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused about 2 million infections and is responsible for more than 100,000 deaths worldwide. To date, there is no specific drug registered to combat the disease it causes, named coronavirus disease 2019 (COVID-19). In the current study, we used an in silico approach to screen natural compounds to find potent inhibitors of the host enzyme transmembrane protease serine 2 (TMPRSS2). This enzyme facilitates viral particle entry into host cells, and its inhibition blocks virus fusion with angiotensin-converting enzyme 2 (ACE2). This, in turn, restricts SARS-CoV-2 pathogenesis. A three-dimensional structure of TMPRSS2 was built using SWISS-MODEL and validated by RAMPAGE. The natural compounds library Natural Product Activity and Species Source (NPASS), containing 30,927 compounds, was screened against the target protein. Two techniques were used in the Molecular Operating Environment (MOE) for this purpose, i.e., a ligand-based pharmacophore approach and a molecular docking-based screening. In total, 2140 compounds with pharmacophoric features were retained using the first approach. Using the second approach, 85 compounds with molecular docking comparable to or greater than that of the standard inhibitor (camostat mesylate) were identified. The top 12 compounds with the most favorable structural features were studied for physicochemical and ADMET (absorption, distribution, metabolism, excretion, toxicity) properties. The low-molecular-weight compound NPC306344 showed significant interaction with the active site residues of TMPRSS2, with a binding energy score of −14.69. Further in vitro and in vivo validation is needed to study and develop an anti-COVID-19 drug based on the structures of the most promising compounds identified in this study. View Full-Text
Keywords: coronavirus; serine protease; natural product; drug design; docking coronavirus; serine protease; natural product; drug design; docking
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MDPI and ACS Style

Rahman, N.; Basharat, Z.; Yousuf, M.; Castaldo, G.; Rastrelli, L.; Khan, H. Virtual Screening of Natural Products against Type II Transmembrane Serine Protease (TMPRSS2), the Priming Agent of Coronavirus 2 (SARS-CoV-2). Molecules 2020, 25, 2271.

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