Disrupting protease and deubiquitinase activities of SARS-CoV-2 papain-like protease by natural and synthetic products discovered through multiple computational and biochemical approaches.

Autor: Waqas M; Department of Biotechnology and Genetic Engineering, Hazara University, Mansehra 2100, Pakistan., Ullah S; Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Sultanate of Oman., Ullah A; Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Sultanate of Oman., Halim SA; Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Sultanate of Oman., Rehman NU; Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Sultanate of Oman., Khalid A; Health Research Center, Jazan University, P.O. Box: 114, Jazan 45142, Saudi Arabia., Ali A; Department of Biotechnology and Genetic Engineering, Hazara University, Mansehra 2100, Pakistan. Electronic address: amjad.genetics@hu.edu.pk., Khan A; Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Sultanate of Oman. Electronic address: ajmalkhan@unizwa.edu.om., Gibbons S; Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Sultanate of Oman., Csuk R; Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany., Al-Harrasi A; Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Sultanate of Oman. Electronic address: aharrasi@unizwa.edu.om.
Jazyk: angličtina
Zdroj: International journal of biological macromolecules [Int J Biol Macromol] 2024 Oct; Vol. 277 (Pt 4), pp. 134476. Date of Electronic Publication: 2024 Aug 05.
DOI: 10.1016/j.ijbiomac.2024.134476
Abstrakt: The single-stranded RNA genome of SARS-CoV-2 encodes several structural and non-structural proteins, among which the papain-like protease (PLpro) is crucial for viral replication and immune evasion and has emerged as a promising therapeutic target. The current study aims to discover new inhibitors of PLpro that can simultaneously disrupt its protease and deubiquitinase activities. Using multiple computational approaches, six compounds (CP1-CP6) were selected from our in-house compounds database, with higher docking scores (-7.97 kcal/mol to -8.14 kcal/mol) and fitted well in the active pocket of PLpro. Furthermore, utilizing microscale molecular dynamics simulations (MD), the dynamic behavior of selected compounds was studied. Those molecules strongly binds at the PLpro active site and forms stable complexes. The dynamic motions suggest that the binding of CP1-CP6 brought the protein to a closed conformational state, thereby altering its normal function. In an in vitro evaluation, CP2 showed the most significant inhibitory potential for PLpro (protease activity = 2.71 ± 0.33 μM and deubiquitinase activity = 3.11 ± 0.75 μM), followed by CP1, CP5, CP4 and CP6. Additionally, CP1-CP6 showed no cytotoxicity at a concentration of 30 μM in the human BJ cell line.
Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest.
(Copyright © 2024. Published by Elsevier B.V.)
Databáze: MEDLINE
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