In Silico Identification of Potential Inhibitors of the SARS-CoV-2 Nucleocapsid Through Molecular Docking-Based Drug Repurposing

Abstract

SARS-CoV-2 is the virus responsible for the COVID-19 pandemic, and its effects on people worldwide continue to grow. Protein-targeted therapeutics are currently unavailable for this virus. As with other coronaviruses, the nucleocapsid (N) protein is the most conserved RNA-binding structural protein of SARS-CoV-2. The N protein is an appealing target because of its functional role in viral transcription and replication. Therefore, molecular docking method for structure-based drug design was used to investigate the binding energy and binding modes of various anti-N inhibitors in depth. The inhibitors selected were originally developed to target stress granules and other molecules involved in RNA biology, and were either FDA-approved or in the process of clinical trials for COVID-19. We aimed at targeting the N-terminal RNA binding domain (NTD) for molecular docking-based screening, on the basis of the first resolved crystal structure of SARS-CoV-2 N protein (PDB ID: 6M3M) and C-terminal domain (CTD) dimerization of the nucleocapsid phosphoprotein of SARS-COV-2 (PDB ID: 6WJI). Silmitasertib, nintedanib, ternatin, luteolin, and fedratinib were found to interact with RNA binding sites and to form a predicted protein interface with high binding energy. Similarly, silmitasertib, sirolimus-rapamycin, dovitinib, nintedanib, and fedratinib were found to interact with the SARS-CoV-2 N protein at its CTD dimerization sites, according to previous studies. In addition, we investigated an information gap regarding the relationships among the energetic landscape and stability and drug binding of the SARS-CoV-2 N NTD and CTD. Our in silico results clearly indicated that several tested drugs as potent putative inhibitors for COVID-19 therapeutics, thus indicating that they should be further validated as treatments to slow the spread of SARS-CoV-2.

Porphyrin-derived carbon dots for an enhanced antiviral activity targeting the CTD of SARS-CoV-2 nucleocapsid

“…Porphyrin could spontaneously bind to the SARS-CoV-2 N-CTD (binding affinity energy of − 8.6 kcal/mol). The value is comparable to several COVID-19 antiviral candidates targeting the same viral protein, including silmitasertib (− 7.89 kcal/mol), fedratinib (− 8.2 kcal/mol), nintedanib (− 8.4 kcal/mol), dovitinib (− 8.6 kcal/mol), and rapamycin (− 8.9 kcal/ mol), even higher than TMCB (− 7.05 kcal/mol), lopinavir (− 6.58 kcal/mol), sapanisertib (− 6.14 kcal/mol), chloroquine (− 5.62 kcal/mol), Arbidol (− 5.32 kcal/ mol), oseltamivir (− 5.08 kcal/mol), ribavirin (− 4.86 kcal/ mol), favipiravir (− 4.44 kcal/mol), hydroxychloroquine (− 4.32 kcal/mol), and remdesivir (− 3.46 kcal/mol) [40][41][42]. Further, as shown in Fig.…”

“…Yuan et al [53] demonstrated the ability to screen drugs inhibiting SARS-CoV-2 replication using pseudovirus, thus greatly reducing the risk of infection during experiments. For future works, we suggested the application of this coronaviral nucleocapsid-targeting DBSS approach to explore the antiviral activities of different types of bioactive compounds other than phytochemicals, such as microbial metabolites [54], and for drug repurposing endeavors [40][41][42].…”

Main and papain-like proteases as prospective targets for pharmacological treatment of coronavirus SARS-CoV-2

“…45 Since the beginning of the pandemic, some in silico studies have been conducted to identify potential SARS-CoV-2 nucleocapsid inhibitors using molecular docking-based drug repurposing. 46,47 At the same time, such research did not lead to the development of drugs of such a focus. One of the reasons for the failure of developing small-molecule therapeutics based on nucleocapsid proteins might be the lack of well-dened binding and catalytic sites.…”