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Supercomputing, Docking and Quantum Mechanics in Quest for Inhibitors of Papain-like Protease of SARS-CoV-2

ABSTRACT: Lomonosov-2 supercomputer is used to search for new organic compounds that can suppress the replication of the SARS-CoV-2 coronavirus. The latter is responsible for the COVID-19 pandemic. Docking and a quantum-chemical semiempirical atomistic modeling method are used to find inhibitors of the SARS-CoV-2 papain-like protease, which is one of the key coronavirus enzymes responsible for its replication. The atomistic model of the papain-like protease of this coronavirus is based on the high-resolution structure deposited in the Protein Data Bank. The SOL docking program has been used for virtual screening of more than

SUBMITTER: Sulimov A

PROVIDER: S-EPMC8351772 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Molecular docking of potential SARS-CoV-2 papain-like protease inhibitors.

Project description:SARS-CoV-2 papain-like protease is considered as an important potential target for anti-SARS-CoV-2 drug discovery due to its crucial roles in viral spread and innate immunity. Here, we have utilized an in silico molecular docking approach to identify the possible inhibitors of the SARS-CoV-2 papain-like protease, by screening 21 antiviral, antifungal and anticancer compounds. Among them, Neobavaisoflavone has the highest binding energy for SARS-CoV-2 papain-like protease. These molecules could bind near the SARS-CoV-2 papain-like protease crucial catalytic triad, ubiquitination and ISGylation residues: Trp106, Asn109, Cys111, Met208, Lys232, Pro247, Tyr268, Gln269, His272, Asp286 and Thr301. Because blocking the papain-like protease is an important strategy in fighting against viruses, these compounds might be promising candidates for therapeutic intervention against COVID-19.

| S-EPMC7698687 | biostudies-literature

Can Papain-like Protease Inhibitors Halt SARS-CoV-2 Replication?

Project description:SARS-CoV-2 encoded papain-like protease (PLpro) harbors a labile Zn site (Cys189-X-X-Cys192-X n -Cys224-X-Cys226) and a classic catalytic site (Cys111-His272-Asp286), which play key roles for viral replication and hence represent promising drug targets. In this Viewpoint, both sulfur-based drugs and peptides-based inhibitors may block Cys residues in the catalytic and/or Zn site of CoV-2-PLpro, leading to dysfunction of CoV-2-PLpro and thereby halting viral replication.

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Validation and Invalidation of SARS-CoV-2 Papain-like Protease Inhibitors

Project description:SARS-CoV-2 encodes two viral cysteine proteases, the main protease (Mpro)

| S-EPMC8806001 | biostudies-literature

SARS-CoV-2 Papain-Like Protease Potential Inhibitors-In Silico Quantitative Assessment.

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes the papain-like protease (PLpro). The protein not only plays an essential role in viral replication but also cleaves ubiquitin and ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from host proteins, making it an important target for developing new antiviral drugs. In this study, we searched for novel, noncovalent potential PLpro inhibitors by employing a multistep in silico screening of a 15 million compound library. The selectivity of the best-scored compounds was evaluated by checking their binding affinity to the human ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), which, as a deubiquitylating enzyme, exhibits structural and functional similarities to the PLpro. As a result, we identified 387 potential, selective PLpro inhibitors, from which we retrieved the 20 best compounds according to their IC50 values toward PLpro estimated by a multiple linear regression model. The selected candidates display potential activity against the protein with IC50 values in the nanomolar range from approximately 159 to 505 nM and mostly adopt a similar binding mode to the known, noncovalent SARS-CoV-2 PLpro inhibitors. We further propose the six most promising compounds for future in vitro evaluation. The results for the top potential PLpro inhibitors are deposited in the database prepared to facilitate research on anti-SARS-CoV-2 drugs.

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Natural biflavones are potent inhibitors against SARS-CoV-2 papain-like protease.

Project description:Papain-like protease (PLpro) is a key enzyme encoded by SARS-CoV-2 that is essential for viral replication and immune evasion. Significant suppression of viral spread and promotion of antiviral immunity can be achieved by inhibition of PLpro, revealing an inspiring strategy for COVID-19 treatment. This study aimed to discover PLpro inhibitors by investigating the national compound library of traditional Chinese medicines (NCLTCMs), a phytochemical library comprising over 9000 TCM-derived compounds. Through virtual screening and enzymatic evaluations, nine natural biflavones were confirmed to be effective PLpro inhibitors with IC50 values ranging from 9.5 to 43.2 μM. Pro-ISG15 cleavage assays further demonstrated that several biflavones exhibited potent inhibitory effects against PLpro-mediated deISGylation, a key process involved in viral immune evasion. Herein, we report the discovery, antiviral evaluation, structure-activity relationship elucidation and molecular docking investigation of biflavones as potent inhibitors of SARS-CoV-2 PLpro.

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Identification of potential inhibitors of SARS-CoV-2 papain-like protease from tropane alkaloids from Schizanthus porrigens: A molecular docking study.

Project description:This paper presents identification of potential inhibitors of SARS-CoV-2 papain-like protease from tropane alkaloids from Schizanthus porrigens, using molecular docking method. Binding affinities were compared with those obtained with Lopinavir as a SARS-CoV-2 papain-like protease inhibitor. Overall, our findings indicate that Schizanthine Z binds to the SARS-CoV-2 papain-like protease with relatively high affinity and favorable ADME properties. Therefore, Schizanthine Z may represent an appropriate compound for further evaluation in antiviral assays.

| S-EPMC7540197 | biostudies-literature

Potent and Selective Covalent Inhibitors of the Papain-like Protease from SARS-CoV-2.

Project description:Direct-acting antivirals for the treatment of COVID-19, which is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), are needed to complement vaccination efforts. The papain-like protease (PLpro) of SARS-CoV-2 is essential for viral proliferation. In addition, PLpro dysregulates the host immune response by cleaving ubiquitin and interferon-stimulated gene 15 protein (ISG15) from host proteins. As a result, PLpro is a promising target for inhibition by small-molecule therapeutics. Here we have designed a series of covalent inhibitors by introducing a peptidomimetic linker and reactive electrophilic "warheads" onto analogs of the noncovalent PLpro inhibitor GRL0617. We show that the most promising PLpro inhibitor is potent and selective, with activity in cell-based antiviral assays rivaling that of the RNA-dependent RNA polymerase inhibitor remdesivir. An X-ray crystal structure of the most promising lead compound bound covalently to PLpro establishes the molecular basis for protease inhibition and selectivity against structurally similar human deubiquitinases. These findings present an opportunity for further development of potent and selective covalent PLpro inhibitors.

| S-EPMC8509099 | biostudies-literature

Identification of SARS-CoV-2 Papain-like Protease (PLpro) Inhibitors Using Combined Computational Approach.

Project description:In the current pandemic, finding an effective drug to prevent or treat the infection is the highest priority. A rapid and safe approach to counteract COVID-19 is in silico drug repurposing. The SARS-CoV-2 PLpro promotes viral replication and modulates the host immune system, resulting in inhibition of the host antiviral innate immune response, and therefore is an attractive drug target. In this study, we used a combined in silico virtual screening for candidates for SARS-CoV-2 PLpro protease inhibitors. We used the Informational spectrum method applied for Small Molecules for searching the Drugbank database followed by molecular docking. After in silico screening of drug space, we identified 44 drugs as potential SARS-CoV-2 PLpro inhibitors that we propose for further experimental testing.

| S-EPMC8805381 | biostudies-literature

Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2

Project description:The SARS-CoV-2 coronavirus encodes an essential papain-like protease domain as part of its non-structural protein (nsp)-3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin-like ISG15 protein modifications as well as, with lower activity, Lys48-linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. To identify PLpro inhibitors in a repurposing approach, screening of 3727 unique approved drugs and clinical compounds against SARS2 PLpro, identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, non-covalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent selfprocessing of nsp3 in cells, and display high potency and excellent antiviral activity in a SARS-CoV-2 infection model.

| S-SCDT-EMBOJ-2020-106275 | biostudies-other

<i>In silico</i> Exploration of Inhibitors for SARS-CoV-2's Papain-Like Protease.

Project description:Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with very limited treatments so far. Demonstrated with good druggability, two major proteases of SARS-CoV-2, namely main protease (Mpro) and papain-like protease (PLpro) that are essential for viral maturation, have become the targets for many newly designed inhibitors. Unlike Mpro that has been heavily investigated, PLpro is not well-studied so far. Here, we carried out the in silico high-throughput screening of all FDA-approved drugs via the flexible docking simulation for potential inhibitors of PLpro and explored the molecular mechanism of binding between a known inhibitor rac5c and PLpro. Our results, from molecular dynamics simulation, show that the chances of drug repurposing for PLpro might be low. On the other hand, our long (about 450 ns) MD simulation confirms that rac5c can be bound stably inside the substrate-binding site of PLpro and unveils the molecular mechanism of binding for the rac5c-PLpro complex. The latter may help perform further structural optimization and design potent leads for inhibiting PLpro.

| S-EPMC7889802 | biostudies-literature

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