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Dual targeting of 3CL^pro and PL^pro of SARS-CoV-2: A novel structure-based design approach to treat COVID-19.

ABSTRACT: With the rapid growth of the COVID-19 (coronavirus disease 2019) pandemic across the globe, therapeutic attention must be directed to fight the novel severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). However, developing new antiviral drugs and vaccines is time-consuming, so one of the best solutions to tackle this virus at present is to repurpose ready-to-use drugs. This paper proposes the repurposing of the Food and Drug Administration (FDA)-approved, purchasable, and naturally occurring drugs for preventive and therapeutic use. We propose to design a dual-inhibitor for the SARS-CoV-2 cysteine proteases-3 Chemotrypsin-like protease or main protease (3CL^pro or M^pro) and Papain-like protease (PL^pro) responsible for processing the translated polyprotein chain from the viral RNA yielding functional viral proteins. For virtual screening, an unbiased blind docking was performed from which the top nine dual-targeting inhibitors for 3CL^pro and PL^pro were selected. The nine repurposed drugs, block the catalytic dyad (His41 and Cys145) of 3CL^pro as well as the catalytic triad (Cys111, His272, and Asp286) of PL^pro. Repurposing known drugs will not only pave the way for rapid in-vitro and in-vivo studies to battle the SARS-CoV-2 but will also expedite the quest for a potent anti-coronaviral drug.

SUBMITTER: Rajpoot S

PROVIDER: S-EPMC7726703 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Virtual high throughput screening: Potential Inhibitors for SARS-CoV-2 PLPRO and 3CLPRO Proteases.

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Effects of diarylbutane lignans from Schisandra chinensis fruit on SARS-CoV-2 3CLpro and PLpro and their in vitro anti-inflammatory properties.

Project description:BackgroundSchisandra chinensis fruit is a well-known traditional Chinese medicine (TCM), whose extract has a potent inhibitory effect on the severe acute respiratory syndrome-coronavirus-2 (SARS‑CoV‑2) 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro).PurposeThis work aims to find the active components from the fruit of S. chinensis against SARS‑CoV‑2 3CLpro and PLpro.Materials and methodsThe chemical constituents of the fruit of S. chinensis were retrieved based on the electronic databases, such as Web of Science, PubMed, Medline Plus, and CNKI. Molecular docking was used to screen the active components against SARS‑CoV‑2 3CLpro and PLpro. Potential hit compounds were further evaluated by enzymatic activity assay. Furthermore, the anti-inflammatory activities of the active compounds were further explored using the phorbol-12-myristate-13-acetate (PMA)-induced THP1 cells model.ResultsIn this work, we retrieved 75 components of S. chinensis fruit, including 62 dibenzocyclooctadiene-type lignans, 3 diarylbutane-type lignans, 2 tetrahydrofuran-type lignans, and 8 nortriterpenoids. Combining molecular docking study and in vitro experiments, we found that pregomisin (63), meso‑dihydroguaiaretic acid (64), and nordihydroguaiaretic acid (65) could potently inhibit 3CLpro with IC50 values of 3.07 ± 0.38, 4.12 ± 0.38, and 6.06 ± 0.62 μM, respectively, and inhibit PLpro with IC50 values of 5.23 ± 0.33, 4.24 ± 0.46, and 16.28 ± 0.54 μM, respectively. Interestingly, compounds 63, 64, and 65 also have potent activities of regulating the inflammatory response in vitro.ConclusionOur results suggest that compounds 63, 64, and 65 may be promising SARS-CoV-2 3CLpro and PLpro inhibitors and anti-inflammatory.

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