Targeting SARS-CoV-2 nucleocapsid oligomerization: Insights from molecular docking and molecular dynamics simulations

Abstract

The outbreak of COVID-19 caused by SARS-CoV-2 virus continually led to infect a large population worldwide. Currently, there is no specific viral protein-targeted therapeutics. The Nucleocapsid (N) protein of the SARS-CoV-2 virus is necessary for viral RNA replication and transcription. The C-terminal domain of N protein (CTD) involves in the self-assembly of N protein into a filament that is packaged into new virions. In this study, the CTD (PDB ID: 6WJI) was targeted for the identification of possible inhibitors of oligomerization of N protein. Herein, multiple computational approaches were employed to explore the potential mechanisms of binding and inhibitor activity of five antiviral drugs toward CTD. The five anti-N drugs studied in this work are 4E1RCat, Silmitasertib, TMCB, Sapanisertib, and Rapamycin. Among the five drugs, 4E1RCat displayed highest binding affinity (-10.95 kcal/mol), followed by rapamycin (-8.91 kcal/mol), silmitasertib (-7.89 kcal/mol), TMCB (-7.05 kcal/mol), and sapanisertib (-6.14 kcal/mol). Subsequently, stability and dynamics of the protein-drug complex were examined with molecular dynamics (MD) simulations. Overall, drug binding increases the stability of the complex with maximum stability observed in the case of 4E1RCat. The CTD-drug complex systems behave differently in terms of the free energy landscape and showed differences in population distribution. Overall, the MD simulation parameters like RMSD, RMSF, Rg, hydrogen bonds analysis, PCA, FEL, and DCCM analysis indicated that 4E1RCat and TMCB complexes were more stable as compared to silmitasertib and sapanisertib and thus could act as effective drug compounds against CTD.

In-vitro acetylation of SARS-CoV and SARS-CoV-2 nucleocapsid proteins by human PCAF and GCN5

“…The N proteins of SARS-CoV and SARS-CoV-2 consist of N- and C-terminal domains separated by a serine-rich linker domain [ 26 , 27 ]. The N- and C-terminal domains are known to possess an RNA-binding domain and an oligomerization domain, respectively [ [28] , [29] , [30] , [31] ]. Partial tertiary structures of the N - and C -terminal domains of SARS-CoV and SARS-CoV-2 N proteins have been reported [ [31] , [32] , [33] ].…”

“…(A) Ribbon diagram of the SARS-CoV-2 N protein N -terminal domain containing the RNA binding surface (PDB ID: 6M3M ) [ 33 ]. The RNA interaction surface is constructed with the “basic finger” and the “basic palm” [ 30 ]. Two acetylation targets, K100 and K102, were contained in the long basic β-hairpin (β2′ and β3′) constructing the basic finger.…”

Energetic and structural features of SARS-CoV-2 N-protein co-assemblies with nucleic acids

“…Structures and dynamics of both CTD and NTD, isolated or in complex with NA, have been studied and reveal significant molecular details (Ahamad et al, 2020; Caruso et al, 2020; Chen et al, 2007; Dinesh et al, 2020; Kang et al, 2020; Takeda et al, 2008; Zinzula et al, 2020). Intriguingly, it was reported recently by several laboratories that N-protein undergoes liquid-liquid phase separation (LLPS) (Carlson et al, 2020; Cascarina and Ross, 2020; Chen et al, 2020a; Cubuk et al, 2020; Iserman et al, 2020; Jack et al, 2020; Lu et al, 2020; Perdikari et al, 2020; Savastano et al, 2020; Wang et al, 2021; Zhao et al, 2020).…”

Rapamycin: Drug Repurposing in SARS-CoV-2 Infection

“…Ahamad et al [ 18 ] used multiple computational approaches to explore the potential mechanisms of binding and inhibitor activity of several compounds toward C-terminal domain (CTD) of N protein. Among the drugs, rapamycin displayed the second highest binding affinity (−8.91 kcal/mol) [ 22 ]. Moreover, Tatar et al [ 23 ] investigated 34 existing antiviral compounds in docking study on the N protein of SARS-CoV-2.…”

“…Maiese [ 21 ] in the review showed that mTOR pathways in conjunction with AMPK may offer valuable targets to control cell injury, oxidative stress, mitochondrial dysfunction and the onset of hyperinflammation, a significant disability associated with COVID-19. Zhavoronkov [ 22 ] points out that the COVID-19 infection rates, severity and lethality are substantially higher in the population aged 60 and older. The author discusses this topic from the point of age and some geroprotectors, such as rapamycin and its analogues.…”