Structure-Based Virtual Screening for Methyltransferase Inhibitors of SARS-CoV-2 nsp14 and nsp16

Wu, Kejue; Guo, Yinfeng; Xu, Tiefeng; Huang, Weifeng; Guo, Deyin; Cao, Liu; Lei, Jinping

doi:10.3390/molecules29102312

Open AccessArticle

Structure-Based Virtual Screening for Methyltransferase Inhibitors of SARS-CoV-2 nsp14 and nsp16

by

Kejue Wu

^1,†,

Yinfeng Guo

^1,†,

Tiefeng Xu

²,

Weifeng Huang

¹

,

Deyin Guo

^2,3,

Liu Cao

² and

Jinping Lei

^1,*

¹

Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China

²

Centre for Infection and Immunity Studies (CIIS), School of Medicine, Sun Yat-Sen University, Shenzhen 518107, China

³

Guangzhou Laboratory, Bio-Island, Guangzhou 510320, China

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Molecules 2024, 29(10), 2312; https://doi.org/10.3390/molecules29102312

Submission received: 29 January 2024 / Revised: 6 April 2024 / Accepted: 18 April 2024 / Published: 15 May 2024

(This article belongs to the Special Issue Computational Approaches in Drug Discovery and Design)

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Abstract

The ongoing COVID-19 pandemic still threatens human health around the world. The methyltransferases (MTases) of SARS-CoV-2, specifically nsp14 and nsp16, play crucial roles in the methylation of the N7 and 2′-O positions of viral RNA, making them promising targets for the development of antiviral drugs. In this work, we performed structure-based virtual screening for nsp14 and nsp16 using the screening workflow (HTVS, SP, XP) of Schrödinger 2019 software, and we carried out biochemical assays and molecular dynamics simulation for the identification of potential MTase inhibitors. For nsp14, we screened 239,000 molecules, leading to the identification of three hits A1–A3 showing N7-MTase inhibition rates greater than 60% under a concentration of 50 µM. For the SAM binding and nsp10-16 interface sites of nsp16, the screening of 210,000 and 237,000 molecules, respectively, from ZINC15 led to the discovery of three hit compounds B1–B3 exhibiting more than 45% of 2′-O-MTase inhibition under 50 µM. These six compounds with moderate MTase inhibitory activities could be used as novel candidates for the further development of anti-SARS-CoV-2 drugs.

Keywords: SARS-CoV-2; nsp14; nsp16; MTase inhibitors; structure-based virtual screening

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MDPI and ACS Style

Wu, K.; Guo, Y.; Xu, T.; Huang, W.; Guo, D.; Cao, L.; Lei, J. Structure-Based Virtual Screening for Methyltransferase Inhibitors of SARS-CoV-2 nsp14 and nsp16. Molecules 2024, 29, 2312. https://doi.org/10.3390/molecules29102312

AMA Style

Wu K, Guo Y, Xu T, Huang W, Guo D, Cao L, Lei J. Structure-Based Virtual Screening for Methyltransferase Inhibitors of SARS-CoV-2 nsp14 and nsp16. Molecules. 2024; 29(10):2312. https://doi.org/10.3390/molecules29102312

Chicago/Turabian Style

Wu, Kejue, Yinfeng Guo, Tiefeng Xu, Weifeng Huang, Deyin Guo, Liu Cao, and Jinping Lei. 2024. "Structure-Based Virtual Screening for Methyltransferase Inhibitors of SARS-CoV-2 nsp14 and nsp16" Molecules 29, no. 10: 2312. https://doi.org/10.3390/molecules29102312

APA Style

Wu, K., Guo, Y., Xu, T., Huang, W., Guo, D., Cao, L., & Lei, J. (2024). Structure-Based Virtual Screening for Methyltransferase Inhibitors of SARS-CoV-2 nsp14 and nsp16. Molecules, 29(10), 2312. https://doi.org/10.3390/molecules29102312

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Structure-Based Virtual Screening for Methyltransferase Inhibitors of SARS-CoV-2 nsp14 and nsp16

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