Identification of potential SARS-CoV-2 papain-like protease inhibitors with the ability to interact with the catalytic triad

Murtala Muhammad; I. Y. Habib; Abdulmumin Yunusa; Tasiu A. Mikail; A. J. ALhassan; Ahed J. Alkhatib; Hamza Sule; Sagir Y. Ismail; Dong Liu; Murtala Muhammad; I. Y. Habib; Abdulmumin Yunusa; Tasiu A. Mikail; A. J. ALhassan; Ahed J. Alkhatib; Hamza Sule; Sagir Y. Ismail; Dong Liu

doi:10.3934/biophy.2023005

AIMS Biophysics

2023, Volume 10, Issue 1: 50-66. doi: 10.3934/biophy.2023005

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Identification of potential SARS-CoV-2 papain-like protease inhibitors with the ability to interact with the catalytic triad

1.
Department of Biochemistry, Kano University of Science and Technology, Wudil, Nigeria
2.
College of Life Science, Hebei Normal University, 050024 Shijiazhuang, China
3.
Department of Chemistry, Sa'adatu Rimi College of Education Kumbotso, Kano, Nigeria
4.
Department of Biochemistry, Bayero University Kano, Nigeria
5.
Faculty of Medicine, Jordan University of Science and Technology, Jordan
6.
Department of Applied Medical Science, Bayero University, Kano, Nigeria

Received: 04 September 2022 Revised: 23 October 2022 Accepted: 31 October 2022 Published: 30 January 2023

Severe acute respiratory syndrome corona virus2 (SARS-CoV-2) is responsible for the current pandemic that led to so many deaths across the globe and still has no effective medication. One attractive target is Papain-like protease (PLpro), which plays a critical role in viral replication. Several important structural features dictate access to the PLpro narrow active site, which includes a series of loops surrounding the area. As such, it is difficult for chemical compounds to fit the SARS-CoV-2 PLpro active site. This work employed a computational study to discover inhibitors that could bind to the SARS-COV-2 PLpro active site, mainly by virtual screening, molecular dynamic simulation, MMPBSA and ADMET analysis. Eight potential inhibitors were identified: carbonoperoxoic acid, Chrysophanol-9-anthrone, Adrenolutin, 1-Dehydroprogesterone, Cholest-22-ene-21-ol, Cis-13-Octadecenoic acid, Hydroxycarbonate and 1-(4-(4-Methylphenyl)-5-phenyl-1,3-oxazol-2-yl) isoquinoline, with binding scores of −4.4, −6.7, −5.9, −6.7, −7.0, −4.6, −4.5 and −5.6 kcal/mol, respectively. All these compounds interacted with critical PLpro catalytic residues and showed stable conformation in molecular dynamics simulations with significant binding energies of −12.73 kcal/mol, −10.89 kcal/mol, −7.20 kcal/mol, −16.25 kcal/mol, −19.00 kcal/mol, −5.00 kcal/mol, −13.21 kcal/mol and −12.45 kcal/mol, respectively, as revealed by MMPBSA analysis. ADMET analysis also indicated that they are safe for drug development. In this study, we identified novel compounds that interacted with the key catalytic residues of SARS-CoV-2 PLpro with the potential to be utilized for anti-Covid-19 drug development.
- SARS-CoV-2,
- PLpro,
- inhibitors,
- molecular docking,
- molecular dynamics simulations,
- MMPBSA
Citation: Murtala Muhammad, I. Y. Habib, Abdulmumin Yunusa, Tasiu A. Mikail, A. J. ALhassan, Ahed J. Alkhatib, Hamza Sule, Sagir Y. Ismail, Dong Liu. Identification of potential SARS-CoV-2 papain-like protease inhibitors with the ability to interact with the catalytic triad[J]. AIMS Biophysics, 2023, 10(1): 50-66. doi: 10.3934/biophy.2023005

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Abstract

Severe acute respiratory syndrome corona virus2 (SARS-CoV-2) is responsible for the current pandemic that led to so many deaths across the globe and still has no effective medication. One attractive target is Papain-like protease (PLpro), which plays a critical role in viral replication. Several important structural features dictate access to the PLpro narrow active site, which includes a series of loops surrounding the area. As such, it is difficult for chemical compounds to fit the SARS-CoV-2 PLpro active site. This work employed a computational study to discover inhibitors that could bind to the SARS-COV-2 PLpro active site, mainly by virtual screening, molecular dynamic simulation, MMPBSA and ADMET analysis. Eight potential inhibitors were identified: carbonoperoxoic acid, Chrysophanol-9-anthrone, Adrenolutin, 1-Dehydroprogesterone, Cholest-22-ene-21-ol, Cis-13-Octadecenoic acid, Hydroxycarbonate and 1-(4-(4-Methylphenyl)-5-phenyl-1,3-oxazol-2-yl) isoquinoline, with binding scores of −4.4, −6.7, −5.9, −6.7, −7.0, −4.6, −4.5 and −5.6 kcal/mol, respectively. All these compounds interacted with critical PLpro catalytic residues and showed stable conformation in molecular dynamics simulations with significant binding energies of −12.73 kcal/mol, −10.89 kcal/mol, −7.20 kcal/mol, −16.25 kcal/mol, −19.00 kcal/mol, −5.00 kcal/mol, −13.21 kcal/mol and −12.45 kcal/mol, respectively, as revealed by MMPBSA analysis. ADMET analysis also indicated that they are safe for drug development. In this study, we identified novel compounds that interacted with the key catalytic residues of SARS-CoV-2 PLpro with the potential to be utilized for anti-Covid-19 drug development.

Conflict of interest

The authors declare no conflict of interest.

Author contributions

MM, IYH and DL: conceptualization, methodology, writing of the original draft, editing and reviewing; AY, AJA and SYI: writing of the original draft, methodology; TAM, AJ and HS: methodology and writing of the original draft. All authors have read and approved the manuscript.

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