Combining virtual screening with cis-/trans-cleavage enzymatic assays effectively reveals broad-spectrum inhibitors that target the main proteases of SARS-CoV-2 and MERS-CoV

Yu Jen Chang; Uyen Nguyen Phuong Le; Jia Jun Liu; Sin Rong Li; Shao Ting Chao; Hsueh Chou Lai; Yu Feng Lin; Kai Cheng Hsu; Chih Hao Lu; Cheng Wen Lin

doi:10.1016/j.antiviral.2023.105653

Combining virtual screening with cis-/trans-cleavage enzymatic assays effectively reveals broad-spectrum inhibitors that target the main proteases of SARS-CoV-2 and MERS-CoV

Yu Jen Chang, Uyen Nguyen Phuong Le, Jia Jun Liu, Sin Rong Li, Shao Ting Chao, Hsueh Chou Lai, Yu Feng Lin, Kai Cheng Hsu, Chih Hao Lu^*, Cheng Wen Lin^*

^*Corresponding author for this work

Institute of Bioinformatics and Systems Biology

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

The main protease (M^pro) of SARS-CoV-2 is essential for viral replication, which suggests that the M^pro is a critical target in the development of small molecules to treat COVID-19. This study used an in-silico prediction approach to investigate the complex structure of SARS-CoV-2 M^pro in compounds from the United States National Cancer Institute (NCI) database, then validate potential inhibitory compounds against the SARS-CoV-2 M^pro in cis- and trans-cleavage proteolytic assays. Virtual screening of ∼280,000 compounds from the NCI database identified 10 compounds with highest site-moiety map scores. Compound NSC89640 (coded C1) showed marked inhibitory activity against the SARS-CoV-2 M^pro in cis-/trans-cleavage assays. C1 strongly inhibited SARS-CoV-2 M^pro enzymatic activity, with a half maximal inhibitory concentration (IC₅₀) of 2.69 μM and a selectivity index (SI) of >74.35. The C1 structure served as a template to identify structural analogs based on AtomPair fingerprints to refine and verify structure-function associations. M^pro-mediated cis-/trans-cleavage assays conducted with the structural analogs revealed that compound NSC89641 (coded D2) exhibited the highest inhibitory potency against SARS-CoV-2 M^pro enzymatic activity, with an IC₅₀ of 3.05 μM and a SI of >65.57. Compounds C1 and D2 also displayed inhibitory activity against MERS-CoV-2 with an IC₅₀ of <3.5 μM. Thus, C1 shows potential as an effective M^pro inhibitor of SARS-CoV-2 and MERS-CoV. Our rigorous study framework efficiently identified lead compounds targeting the SARS-CoV-2 M^pro and MERS-CoV M^pro.

Original language	English
Article number	105653
Journal	Antiviral Research
Volume	216
DOIs	https://doi.org/10.1016/j.antiviral.2023.105653
State	Published - Aug 2023

Keywords

cis-/trans-cleavage assay
In-silico prediction
Main protease
MERS-CoV
National cancer institute database
SARS-CoV-2

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.antiviral.2023.105653

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Chang, Y. J., Le, U. N. P., Liu, J. J., Li, S. R., Chao, S. T., Lai, H. C., Lin, Y. F., Hsu, K. C., Lu, C. H., & Lin, C. W. (2023). Combining virtual screening with cis-/trans-cleavage enzymatic assays effectively reveals broad-spectrum inhibitors that target the main proteases of SARS-CoV-2 and MERS-CoV. Antiviral Research, 216, Article 105653. https://doi.org/10.1016/j.antiviral.2023.105653

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title = "Combining virtual screening with cis-/trans-cleavage enzymatic assays effectively reveals broad-spectrum inhibitors that target the main proteases of SARS-CoV-2 and MERS-CoV",

abstract = "The main protease (Mpro) of SARS-CoV-2 is essential for viral replication, which suggests that the Mpro is a critical target in the development of small molecules to treat COVID-19. This study used an in-silico prediction approach to investigate the complex structure of SARS-CoV-2 Mpro in compounds from the United States National Cancer Institute (NCI) database, then validate potential inhibitory compounds against the SARS-CoV-2 Mpro in cis- and trans-cleavage proteolytic assays. Virtual screening of ∼280,000 compounds from the NCI database identified 10 compounds with highest site-moiety map scores. Compound NSC89640 (coded C1) showed marked inhibitory activity against the SARS-CoV-2 Mpro in cis-/trans-cleavage assays. C1 strongly inhibited SARS-CoV-2 Mpro enzymatic activity, with a half maximal inhibitory concentration (IC50) of 2.69 μM and a selectivity index (SI) of >74.35. The C1 structure served as a template to identify structural analogs based on AtomPair fingerprints to refine and verify structure-function associations. Mpro-mediated cis-/trans-cleavage assays conducted with the structural analogs revealed that compound NSC89641 (coded D2) exhibited the highest inhibitory potency against SARS-CoV-2 Mpro enzymatic activity, with an IC50 of 3.05 μM and a SI of >65.57. Compounds C1 and D2 also displayed inhibitory activity against MERS-CoV-2 with an IC50 of <3.5 μM. Thus, C1 shows potential as an effective Mpro inhibitor of SARS-CoV-2 and MERS-CoV. Our rigorous study framework efficiently identified lead compounds targeting the SARS-CoV-2 Mpro and MERS-CoV Mpro.",

keywords = "cis-/trans-cleavage assay, In-silico prediction, Main protease, MERS-CoV, National cancer institute database, SARS-CoV-2",

author = "Chang, {Yu Jen} and Le, {Uyen Nguyen Phuong} and Liu, {Jia Jun} and Li, {Sin Rong} and Chao, {Shao Ting} and Lai, {Hsueh Chou} and Lin, {Yu Feng} and Hsu, {Kai Cheng} and Lu, {Chih Hao} and Lin, {Cheng Wen}",

note = "Publisher Copyright: {\textcopyright} 2023 Elsevier B.V.",

year = "2023",

month = aug,

doi = "10.1016/j.antiviral.2023.105653",

language = "English",

volume = "216",

journal = "Antiviral Research",

issn = "0166-3542",

publisher = "Elsevier B.V.",

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TY - JOUR

T1 - Combining virtual screening with cis-/trans-cleavage enzymatic assays effectively reveals broad-spectrum inhibitors that target the main proteases of SARS-CoV-2 and MERS-CoV

AU - Chang, Yu Jen

AU - Le, Uyen Nguyen Phuong

AU - Liu, Jia Jun

AU - Li, Sin Rong

AU - Chao, Shao Ting

AU - Lai, Hsueh Chou

AU - Lin, Yu Feng

AU - Hsu, Kai Cheng

AU - Lu, Chih Hao

AU - Lin, Cheng Wen

PY - 2023/8

Y1 - 2023/8

N2 - The main protease (Mpro) of SARS-CoV-2 is essential for viral replication, which suggests that the Mpro is a critical target in the development of small molecules to treat COVID-19. This study used an in-silico prediction approach to investigate the complex structure of SARS-CoV-2 Mpro in compounds from the United States National Cancer Institute (NCI) database, then validate potential inhibitory compounds against the SARS-CoV-2 Mpro in cis- and trans-cleavage proteolytic assays. Virtual screening of ∼280,000 compounds from the NCI database identified 10 compounds with highest site-moiety map scores. Compound NSC89640 (coded C1) showed marked inhibitory activity against the SARS-CoV-2 Mpro in cis-/trans-cleavage assays. C1 strongly inhibited SARS-CoV-2 Mpro enzymatic activity, with a half maximal inhibitory concentration (IC50) of 2.69 μM and a selectivity index (SI) of >74.35. The C1 structure served as a template to identify structural analogs based on AtomPair fingerprints to refine and verify structure-function associations. Mpro-mediated cis-/trans-cleavage assays conducted with the structural analogs revealed that compound NSC89641 (coded D2) exhibited the highest inhibitory potency against SARS-CoV-2 Mpro enzymatic activity, with an IC50 of 3.05 μM and a SI of >65.57. Compounds C1 and D2 also displayed inhibitory activity against MERS-CoV-2 with an IC50 of <3.5 μM. Thus, C1 shows potential as an effective Mpro inhibitor of SARS-CoV-2 and MERS-CoV. Our rigorous study framework efficiently identified lead compounds targeting the SARS-CoV-2 Mpro and MERS-CoV Mpro.

AB - The main protease (Mpro) of SARS-CoV-2 is essential for viral replication, which suggests that the Mpro is a critical target in the development of small molecules to treat COVID-19. This study used an in-silico prediction approach to investigate the complex structure of SARS-CoV-2 Mpro in compounds from the United States National Cancer Institute (NCI) database, then validate potential inhibitory compounds against the SARS-CoV-2 Mpro in cis- and trans-cleavage proteolytic assays. Virtual screening of ∼280,000 compounds from the NCI database identified 10 compounds with highest site-moiety map scores. Compound NSC89640 (coded C1) showed marked inhibitory activity against the SARS-CoV-2 Mpro in cis-/trans-cleavage assays. C1 strongly inhibited SARS-CoV-2 Mpro enzymatic activity, with a half maximal inhibitory concentration (IC50) of 2.69 μM and a selectivity index (SI) of >74.35. The C1 structure served as a template to identify structural analogs based on AtomPair fingerprints to refine and verify structure-function associations. Mpro-mediated cis-/trans-cleavage assays conducted with the structural analogs revealed that compound NSC89641 (coded D2) exhibited the highest inhibitory potency against SARS-CoV-2 Mpro enzymatic activity, with an IC50 of 3.05 μM and a SI of >65.57. Compounds C1 and D2 also displayed inhibitory activity against MERS-CoV-2 with an IC50 of <3.5 μM. Thus, C1 shows potential as an effective Mpro inhibitor of SARS-CoV-2 and MERS-CoV. Our rigorous study framework efficiently identified lead compounds targeting the SARS-CoV-2 Mpro and MERS-CoV Mpro.

KW - cis-/trans-cleavage assay

KW - In-silico prediction

KW - Main protease

KW - MERS-CoV

KW - National cancer institute database

KW - SARS-CoV-2

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DO - 10.1016/j.antiviral.2023.105653

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AN - SCOPUS:85161962425

SN - 0166-3542

VL - 216

JO - Antiviral Research

JF - Antiviral Research

M1 - 105653

ER -

Combining virtual screening with cis-/trans-cleavage enzymatic assays effectively reveals broad-spectrum inhibitors that target the main proteases of SARS-CoV-2 and MERS-CoV

Abstract

Keywords

UN SDGs

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