SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment

Stasiulewicz, Adam; Maksymiuk, Alicja W.; Nguyen, Mai Lan; Bełza, Barbara; Sulkowska, Joanna I.

doi:10.3390/ijms22083957

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SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment

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Joanna I. Sulkowska

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Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097 Warsaw, Poland

Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland

School of the Biological Sciences, University of Cambridge, 17 Mill Lane, Cambridge CB2 1RX, UK

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Faculty of Mathematics, Informatics and Mechanics, University of Warsaw, Banacha 2, 02-097 Warsaw, Poland

⁵

College of Inter-Faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, Banacha 2c, 02-097 Warsaw, Poland

Author to whom correspondence should be addressed.

Academic Editor: Edmond Ma

Int. J. Mol. Sci. 2021, 22(8), 3957; https://doi.org/10.3390/ijms22083957

Received: 5 March 2021 / Revised: 26 March 2021 / Accepted: 2 April 2021 / Published: 12 April 2021

(This article belongs to the Special Issue New Avenues in Molecular Docking for Drug Design 2021)

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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes the papain-like protease (PLpro). The protein not only plays an essential role in viral replication but also cleaves ubiquitin and ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from host proteins, making it an important target for developing new antiviral drugs. In this study, we searched for novel, noncovalent potential PLpro inhibitors by employing a multistep in silico screening of a 15 million compound library. The selectivity of the best-scored compounds was evaluated by checking their binding affinity to the human ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), which, as a deubiquitylating enzyme, exhibits structural and functional similarities to the PLpro. As a result, we identified 387 potential, selective PLpro inhibitors, from which we retrieved the 20 best compounds according to their IC₅₀ values toward PLpro estimated by a multiple linear regression model. The selected candidates display potential activity against the protein with IC₅₀ values in the nanomolar range from approximately 159 to 505 nM and mostly adopt a similar binding mode to the known, noncovalent SARS-CoV-2 PLpro inhibitors. We further propose the six most promising compounds for future in vitro evaluation. The results for the top potential PLpro inhibitors are deposited in the database prepared to facilitate research on anti-SARS-CoV-2 drugs. View Full-Text

Keywords: SARS-CoV-2; COVID-19; coronavirus; PLpro; papain-like protease; UCH-L1; virtual screening; docking; pharmacophore

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MDPI and ACS Style

Stasiulewicz, A.; Maksymiuk, A.W.; Nguyen, M.L.; Bełza, B.; Sulkowska, J.I. SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment. Int. J. Mol. Sci. 2021, 22, 3957. https://doi.org/10.3390/ijms22083957

AMA Style

Stasiulewicz A, Maksymiuk AW, Nguyen ML, Bełza B, Sulkowska JI. SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment. International Journal of Molecular Sciences. 2021; 22(8):3957. https://doi.org/10.3390/ijms22083957

Chicago/Turabian Style

Stasiulewicz, Adam, Alicja W. Maksymiuk, Mai L. Nguyen, Barbara Bełza, and Joanna I. Sulkowska. 2021. "SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment" International Journal of Molecular Sciences 22, no. 8: 3957. https://doi.org/10.3390/ijms22083957

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SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment

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