Dataset Information

In Silico Analysis of Inhibiting Papain-like Protease from SARS-CoV-2 by Using Plant-Derived Peptides.

ABSTRACT: SARS-CoV-2 is a corona virus that has been the cause for one of the deadliest pandemics of history, started since 2019. Suppressing the activity of the critical enzymes in the SARS-CoV-2 could potentially inhibit a vital step in viral life cycle. Papain-like protease (PLpro) could be regarded as a critical enzyme in viral replication of SARS-CoV-2. In this research, it was aimed to suppress the activity of PLpro enzyme by using potential plant-derived protease inhibitor peptides. For this purpose, 11 plant derived peptides that could potentially inhibit protease activity were selected from literature. The structures of the PLpro and the peptide ligands were acquired from PDB (protein data bank) and after structural optimization, were docked by using HADDOCK 2.4 program. Analyzing the results indicated that VcTI from Veronica hederifolia provides effective molecular interactions at both liable Zn site and classic active site of PLpro, making it a potential inhibitory ligand for this enzyme that could be used for halting the replication of SARS-CoV-2. Molecular dynamic assay confirmed that the selected receptor and ligand complex was stable. Future in vitro and in vivo investigations are required to verify the efficiency of this compound as a potential therapeutic against SARS-CoV-2 infection.

Supplementary information

The online version contains supplementary material available at 10.1007/s10989-021-10331-8.

SUBMITTER: Moradi M

PROVIDER: S-EPMC8655715 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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In Silico Analysis of Inhibiting Papain-like Protease from SARS-CoV-2 by Using Plant-Derived Peptides.

Moradi Mohammad M Golmohammadi Reza R Najafi Ali A Moosazadeh Moghaddam Mehrdad M Fasihi-Ramandi Mahdi M Mirnejad Reza R

International journal of peptide research and therapeutics 20211209 1

SARS-CoV-2 is a corona virus that has been the cause for one of the deadliest pandemics of history, started since 2019. Suppressing the activity of the critical enzymes in the SARS-CoV-2 could potentially inhibit a vital step in viral life cycle. Papain-like protease (PLpro) could be regarded as a critical enzyme in viral replication of SARS-CoV-2. In this research, it was aimed to suppress the activity of PLpro enzyme by using potential plant-derived protease inhibitor peptides. For this purpos ...[more]

PMID: 34903959

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Project description:The SARS-Cov-2 virus, which is evolving continuously and causing adverse effects throughout the world, needs an effective drug molecule for its treatment. There are several receptors of SARS Cov-2 which are targeted for its inhibition by many lead molecules both in-vitro and in-vivo. Papain like Protease (PLpro) is one of the two SARS-Cov-2 proteases that can be used as a drug target for SARS Cov-2. It is a coronavirus enzyme that plays a role in the cleavage and maturation of viral polyproteins, assembly of the replicase-transcriptase complex and disruption of host responses. PLpro has also been linked to the cleavage of proteinaceous post translational modifications on host proteins as a means of evading antiviral immune responses. Structure-based drug discovery can be one of the effective methods to screen for various molecules against the target receptors. In this study, PLpro of SARS CoV-2 was chosen as the target for docking. Forty phytochemicals from various plant sources and four synthetic drugs have been screened for their inhibitory potential against PLpro using AutoDock Vina. Phytochemicals such as Tinosponone, Rhoifolin, Rosmanol, Berberin, Nimbin and two other existing drugs Elbasvir and Declatasvir showed higher inhibitory potential in terms of higher binding affinities. ADME and toxicity analysis were also performed to predict the pharmacokinetics and drug likeliness properties. It was concluded from the study that Tinosponone possesss potential inhibitor property of papain-like proteases (PLpro) of SARS CoV-2. Tinosponone from the plant Tinospora cordifolia had a binding affinity of - 9.3 kcal/mol and obeyed the Lipinski rules, making it an effective lead molecule for treating SARS CoV-2. Molecular Dynamics simulation of Tinosponone with PLpro has proved the stability and validity of the binding with RMSD value in range of 0.2 nm when it was run for 50 ns using GROMACS. Therefore, Tinosponone could be considered as a potential inhibitor of PLpro of SARS CoV-2.

Project description:The coronavirus disease 19 (COVID-19) is a rapidly growing pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Its papain-like protease (SARS-CoV-2 PLpro) is a crucial target to halt virus replication. SARS-CoV PLpro and SARS-CoV-2 PLpro share an 82.9% sequence identity and a 100% sequence identity for the binding site reported to accommodate small molecules in SARS-CoV. The flexible key binding site residues Tyr269 and Gln270 for small-molecule recognition in SARS-CoV PLpro exist also in SARS-CoV-2 PLpro. This inspired us to use the reported small-molecule binders to SARS-CoV PLpro to generate a high-quality DEKOIS 2.0 benchmark set. Accordingly, we used them in a cross-benchmarking study against SARS-CoV-2 PLpro. As there is no SARS-CoV-2 PLpro structure complexed with a small-molecule ligand publicly available at the time of manuscript submission, we built a homology model based on the ligand-bound SARS-CoV structure for benchmarking and docking purposes. Three publicly available docking tools FRED, AutoDock Vina, and PLANTS were benchmarked. All showed better-than-random performances, with FRED performing best against the built model. Detailed performance analysis via pROC-Chemotype plots showed a strong enrichment of the most potent bioactives in the early docking ranks. Cross-benchmarking against the X-ray structure complexed with a peptide-like inhibitor confirmed that FRED is the best-performing tool. Furthermore, we performed cross-benchmarking against the newly introduced X-ray structure complexed with a small-molecule ligand. Interestingly, its benchmarking profile and chemotype enrichment were comparable to the built model. Accordingly, we used FRED in a prospective virtual screen of the DrugBank database. In conclusion, this study provides an example of how to harness a custom-made DEKOIS 2.0 benchmark set as an approach to enhance the virtual screening success rate against a vital target of the rapidly emerging pandemic.

Dataset Information

In Silico Analysis of Inhibiting Papain-like Protease from SARS-CoV-2 by Using Plant-Derived Peptides.

Supplementary information

Publications

In Silico Analysis of Inhibiting Papain-like Protease from SARS-CoV-2 by Using Plant-Derived Peptides.

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