Computer-aided drug design for the pain-like protease (PLpro) inhibitors against SARS-CoV-2

Gao, Hongwei; Dai, Renhui; Su, Ruiling

doi:10.1016/j.biopha.2023.114247

Cited by 8 publications

(4 citation statements)

References 61 publications

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“…Overall, viewing the reversible and irreversible binding of compounds 1-10 with the two targets (3CL Pro and PL Pro ), it can be inferred that the structure-activity relationship (SAR) has played a crucial role that may enable them to act as strong inhibitors and may affect viral replication (Supplementary Tables S29 and S30). Similar to our findings, earlier studies have also reported the crucial role of SAR and the inhibitory effects of drugs on 3CL Pro and PL Pro [69][70][71][72].…”

Section: Discussionsupporting

confidence: 93%

Identification of Phytochemicals from Arabian Peninsula Medicinal Plants as Strong Binders to SARS-CoV-2 Proteases (3CLPro and PLPro) by Molecular Docking and Dynamic Simulation Studies

Saquib,

Bakheit,

Ahmed

et al. 2024

Molecules

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We provide promising computational (in silico) data on phytochemicals (compounds 1–10) from Arabian Peninsula medicinal plants as strong binders, targeting 3-chymotrypsin-like protease (3CLPro) and papain-like proteases (PLPro) of SARS-CoV-2. Compounds 1–10 followed the Lipinski rules of five (RO5) and ADMET analysis, exhibiting drug-like characters. Non-covalent (reversible) docking of compounds 1–10 demonstrated their binding with the catalytic dyad (CYS145 and HIS41) of 3CLPro and catalytic triad (CYS111, HIS272, and ASP286) of PLPro. Moreover, the implementation of the covalent (irreversible) docking protocol revealed that only compounds 7, 8, and 9 possess covalent warheads, which allowed the formation of the covalent bond with the catalytic dyad (CYS145) in 3CLPro and the catalytic triad (CYS111) in PLPro. Root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and radius of gyration (Rg) analysis from molecular dynamic (MD) simulations revealed that complexation between ligands (compounds 7, 8, and 9) and 3CLPro and PLPro was stable, and there was less deviation of ligands. Overall, the in silico data on the inherent properties of the above phytochemicals unravel the fact that they can act as reversible inhibitors for 3CLPro and PLPro. Moreover, compounds 7, 8, and 9 also showed their novel properties to inhibit dual targets by irreversible inhibition, indicating their effectiveness for possibly developing future drugs against SARS-CoV-2. Nonetheless, to confirm the theoretical findings here, the effectiveness of the above compounds as inhibitors of 3CLPro and PLPro warrants future investigations using suitable in vitro and in vivo tests.

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Section: Discussionsupporting

confidence: 93%

Identification of Phytochemicals from Arabian Peninsula Medicinal Plants as Strong Binders to SARS-CoV-2 Proteases (3CLPro and PLPro) by Molecular Docking and Dynamic Simulation Studies

Saquib,

Bakheit,

Ahmed

et al. 2024

Molecules

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“…The PLpro enzyme cleaves the viral poly-proteins, resulting in the liberation of nsp1, nsp2, and nsp3. This step is crucial for the replication of the virus [ 57 , 58 , 59 ].…”

Section: Fluorescence-based Drug Screening Methods For Novel Coronavi...mentioning

confidence: 99%

Development of Fluorescence-Based Assays for Key Viral Proteins in the SARS-CoV-2 Infection Process and Lifecycle

Deng,

Zhang,

Yan

et al. 2024

IJMS

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Since the appearance of SARS-CoV-2 in 2019, the ensuing COVID-19 (Corona Virus Disease 2019) pandemic has posed a significant threat to the global public health system, human health, life, and economic well-being. Researchers worldwide have devoted considerable efforts to curb its spread and development. The latest studies have identified five viral proteins, spike protein (Spike), viral main protease (3CLpro), papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), and viral helicase (Helicase), which play crucial roles in the invasion of SARS-CoV-2 into the human body and its lifecycle. The development of novel anti-SARS-CoV-2 drugs targeting these five viral proteins holds immense promise. Therefore, the development of efficient, high-throughput screening methodologies specifically designed for these viral proteins is of utmost importance. Currently, a plethora of screening techniques exists, with fluorescence-based assays emerging as predominant contenders. In this review, we elucidate the foundational principles and methodologies underpinning fluorescence-based screening approaches directed at these pivotal viral targets, hoping to guide researchers in the judicious selection and refinement of screening strategies, thereby facilitating the discovery and development of lead compounds for anti-SARS-CoV-2 pharmaceuticals.

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“…As a result, specific targeting of the catalytic triad (CYS: 111, HIS: 272, and ASP: 286 of PL pro ) can inhibit its activity, preventing the viral replication and deregulation of biochemical cascades in infected cells. TRP: 93, TRP: 106, ASP: 108, and ASN: 109 are also known to contribute towards PL pro function [132]. The N-terminal ubiquitin-like region (Ubl, β1-3), the helical thumb domain (α2-7), the finger region (β4-7), and the palm region (β8-13) are the four sub-regions that constitute the SARS-CoV-2 PL pro protein.…”

Section: Pl Pro Enzyme Structure and Residue-residue Interactions In ...mentioning

confidence: 99%

Natural Products from Marine Actinomycete Genus Salinispora Might Inhibit 3CLpro and PLpro Proteins of SARS-CoV-2: An In Silico Evidence

Pokharkar,

Zyryanov,

Tsurkan

2023

Microbiology Research

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Among the oldest marine species on the planet, the genus Salinispora is often encountered inhabiting sediments and other marine creatures in tropical and subtropical marine settings. This bacterial genus produces a plethora of natural products. The purpose of this study was to examine the potential for salinispora-based natural products (NPs) to combat the SARS-CoV-2 virus. The RCSB PDB was used to obtain the crystal structures of proteins 3CLpro and PLpro. All 125 NPs were obtained from online databases. Using Autodock Vina software v1.2.0 the molecular docking process was carried out after the proteins and ligands were prepared. Assessments of binding affinities and interacting amino acids were rigorously examined prior to MD simulations. The docking experiments revealed 35 NPs in total for both 3CLpro and PLpro, with high docking scores ranging from −8.0 kcal/mol to −9.0 kcal/mol. However, a thorough binding residue analyses of all docked complexes filtered nine NPs showing strong interactions with HIS: 41 and CYS: 145 of 3CLpro. Whereas, for PLpro, merely six NPs presented good interactions with residues CYS: 111, HIS: 272, and ASP: 286. Further research was conducted on residue–residue and ligand–residue interactions in both the filtered docked complexes and the Apo-protein structures using the Protein Contacts Atlas website. All complexes were found to be stable in CABS-flex 2.0 MD simulations conducted at various time frames (50, 125, 500, and 1000 cycles). In conclusion, salinaphthoquinone B appears to be the most promising metabolite, based on favorable amino acid interactions forming stable confirmations towards 3CLpro and PLpro enzymes, acting as a dual inhibitor.

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Computer-aided drug design for the pain-like protease (PLpro) inhibitors against SARS-CoV-2

Cited by 8 publications

References 61 publications

Identification of Phytochemicals from Arabian Peninsula Medicinal Plants as Strong Binders to SARS-CoV-2 Proteases (3CLPro and PLPro) by Molecular Docking and Dynamic Simulation Studies

Identification of Phytochemicals from Arabian Peninsula Medicinal Plants as Strong Binders to SARS-CoV-2 Proteases (3CLPro and PLPro) by Molecular Docking and Dynamic Simulation Studies

Development of Fluorescence-Based Assays for Key Viral Proteins in the SARS-CoV-2 Infection Process and Lifecycle

Natural Products from Marine Actinomycete Genus Salinispora Might Inhibit 3CLpro and PLpro Proteins of SARS-CoV-2: An In Silico Evidence

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