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Identification, Characterization and Drug Discovery for Novel Target Sites for SARS‐CoV‐2 Proteins

ABSTRACT: The virus SARS‐CoV‐2, the cause of the current COVID‐19 pandemic, is not well understood. It is critical to understand how the viral proteins function and how their function may be modulated. Inhibitors that target these enzymes serve as potential therapeutic interventions against COVID‐19. This work uses artificial intelligence methods developed by us to find sites that other methods may not find and therefore, identify potential exosites, allosteric sites, or other sites of interaction in the structures of viral proteins to serve as new targets for the development of antiviral agents. Large datasets of natural and synthetic compounds are computationally searched for molecules that fit into these alternative sites, and any compounds that fit will be targeted for experimental testing for their ability to inhibit the functions of these viral enzymes. This project uses the unique Partial Order Optimum Likelihood (POOL) machine learning method developed by us to predict multiple types of binding sites in SARS‐CoV‐2 proteins, including catalytic sites, allosteric sites, and other interaction sites. Molecular dynamics simulations are used to generate conformations for ensemble docking. Compounds from large molecular libraries are computationally docked into the predicted sites to identify potentially strong binding ligands. We have identified approximately 10000 potential ligands for more than 50 SARS‐CoV‐2 proteins to date. Candidate ligands to selected SARS‐CoV‐2 proteins are experimentally tested in vitro for binding affinity and the effect of the best‐predicted inhibitors on catalytic activities determined by direct biochemical assays. Compound libraries for the study include selected compounds from the ZINC and Enamine databases; Chemical Abstract Service database compounds and COVID‐specific libraries from Enamine and Life Chemicals.

SUBMITTER: Iyengar S

PROVIDER: S-EPMC8239550 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, is a highly contagious positive-sense RNA virus. Its explosive community spread and the emergence of new mutant strains have created palpable anxiety even in vaccinated people. The lack of effective anticoronavirus therapeutics continues to be a major global health concern, especially due to the high evolution rate of SARS-CoV-2. The nucleocapsid protein (N protein) of SARS-CoV-2 is highly conserved and involved in diverse processes of the virus replication cycle. Despite its critical role in coronavirus replication, N protein remains an unexplored target for anticoronavirus drug discovery. Here, we demonstrate that a novel compound, K31, binds to the N protein of SARS-CoV-2 and noncompetitively inhibits its binding to the 5' terminus of the viral genomic RNA. K31 is well tolerated by SARS-CoV-2-permissive Caco2 cells. Our results show that K31 inhibited SARS-CoV-2 replication in Caco2 cells with a selective index of ~58. These observations suggest that SARS-CoV-2 N protein is a druggable target for anticoronavirus drug discovery. K31 holds promise for further development as an anticoronavirus therapeutic. IMPORTANCE The lack of potent antiviral drugs for SARS-CoV-2 is a serious global health concern, especially with the explosive spread of the COVID-19 pandemic worldwide and the constant emergence of new mutant strains with improved human-to-human transmission. Although an effective coronavirus vaccine appears promising, the lengthy vaccine development processes in general and the emergence of new mutant viral strains with a potential to evade the vaccine always remain a serious concern. The antiviral drugs targeted to the highly conserved targets of viral or host origin remain the most viable and timely approach, easily accessible to the general population, in combating any new viral illness. The majority of anticoronavirus drug development efforts have focused on spike protein, envelope protein, 3CLpro, and Mpro. Our results show that virus-encoded N protein is a novel therapeutic target for anticoronavirus drug discovery. Due to its high conservation, the anti-N protein inhibitors will likely have broad-spectrum anticoronavirus activity.

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Identification, Characterization and Drug Discovery for Novel Target Sites for SARS‐CoV‐2 Proteins

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