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An overview of potential inhibitors targeting non-structural proteins 3 (PL^pro and Mac1) and 5 (3CL^pro/M^pro) of SARS-CoV-2.

ABSTRACT: There is an urgent need to develop effective treatments for coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The rapid spread of SARS-CoV-2 has resulted in a global pandemic that has not only affected the daily lives of individuals but also had a significant impact on the global economy and public health. Although extensive research has been conducted to identify inhibitors targeting SARS-CoV-2, there are still no effective treatment strategies to combat COVID-19. SARS-CoV-2 comprises two important proteolytic enzymes, namely, the papain-like proteinase, located within non-structural protein 3 (nsp3), and nsp5, both of which cleave large replicase polypeptides into multiple fragments that are required for viral replication. Moreover, a domain within nsp3, known as the macrodomain (Mac1), also plays an important role in viral replication. Inhibition of their functions should be able to significantly interfere with the replication cycle of the virus, and therefore these key proteins may serve as potential therapeutic targets. The functions of the above viral targets and their corresponding inhibitors have been summarized in the current review. This review provides comprehensive updates of nsp3 and nsp5 inhibitor development and would help advance the discovery of novel anti-viral therapeutics against SARS-CoV-2.

SUBMITTER: Yan F

PROVIDER: S-EPMC8382591 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

Project description:The pandemic, COVID-19, has spread worldwide and affected millions of people. There is an urgent need, therefore, to find a proper treatment for the novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the causative agent. This paper focuses on identifying inhibitors that target SARS-CoV-2 proteases, PLPRO and 3CLPRO, which control the duplication and manages the life cycle of SARS-CoV-2. We have carried out detailed in silico Virtual high-throughput screening using Food and Drug Administration (FDA) approved drugs from the Zinc database, COVID-19 clinical trial compounds from Pubchem database, Natural compounds from Natural Product Activity and Species Source (NPASS) database and Maybridge database against PLPRO and 3CLPRO proteases. After thoroughly analyzing the screening results, we found five compounds, Bemcentinib, Pacritinib, Ergotamine, MFCD00832476, and MFCD02180753 inhibit PLPRO and six compounds, Bemcentinib, Clofazimine, Abivertinib, Dasabuvir, MFCD00832476, Leuconicine F inhibit the 3CLPRO. These compounds are stable within the protease proteins' active sites at 20ns MD simulation. The stability is revealed by hydrogen bond formations, hydrophobic interactions, and salt bridge interactions. Our study results also reveal that the selected five compounds against PLPRO and the six compounds against 3CLPRO bind to their active sites with good binding free energy. These compounds that inhibit the activity of PLPRO and 3CLPRO may, therefore, be used for treating COVID-19 infection.

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Dual targeting of 3CLpro and PLpro of SARS-CoV-2: A novel structure-based design approach to treat COVID-19.

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Potential inhibitors of SARS-CoV-2 (COVID 19) proteases PLpro and Mpro/ 3CLpro: molecular docking and simulation studies of three pertinent medicinal plant natural components.

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"Identification of Nafamostat and VR23 as COVID-19 drug candidates by targeting 3CLpro and PLpro."

Project description:The sudden increase in the COVID-19 epidemic affected by novel coronavirus 2019 has jeopardized public health worldwide. Hence the necessities of a drug or therapeutic agent that heal SARS-CoV-2 infections are essential requirements. The viral genome encodes a large Polyprotein, further processed by the main protease/ 3C-like protease (3CLpro) and papain-like proteases (PLpro) into 16 nonstructural proteins to form a viral replication complex. These essential functions of 3CLpro and PLpro in virus duplication make these proteases a promising target for discovering potential therapeutic candidates and possible treatment for SARS-CoV-2 infection. This study aimed to screen a unique set of protease inhibitors library against 3CLpro and PLpro of the SARS-CoV-2. A molecular docking study was performed using PyRx to reveal the binding affinity of the selected ligands and molecular dynamic simulations were executed to assess the three-dimensional stability of protein-ligand complexes. The pharmacodynamics parameters of the inhibitors were predicted using admetSAR. The top two ligands (Nafamostat and VR23) based on docking scores were selected for further studies. Selected ligands showed excellent pharmacokinetic properties with proper absorption, bioavailability and minimal toxicity. Due to the emerging and efficiency of remdesivir and dexamethasone in healing COVID-19 patients, ADMET properties of the selected ligands were thus compared with it. MD Simulation studies up to 100 ns revealed the ligands' stability at the target proteins' binding site residues. Therefore, Nafamostat and VR23 may provide potential treatment options against SARS-CoV-2 infections by potentially inhibiting virus duplication though more research is warranted.

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