Abstract
Coronaviruses are known to infect respiratory tract and intestine. These viruses possess highly conserved viral macro domain A1pp having adenosine diphosphate (ADP)-ribose binding and phosphatase activity sites. A1pp inhibits adenosine diphosphate (ADP)-ribosylation in the host and promotes viral infection and pathogenesis. We performed in silico screening of FDA approved drugs and nucleoside analogue library against the recently reported crystal structure of SARS-CoV-2 A1pp domain. Docking scores and interaction profile analyses exhibited strong binding affinity of eleven FDA approved drugs and five nucleoside analogues NA1 (-13.84), nadide (-13.65), citicholine (-13.54), NA2 (-12.42), and NA3 (-12.27). The lead compound NA1 exhibited significant hydrogen bonding and hydrophobic interaction at the natural substrate binding site. The root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent accessible surface (SASA), hydrogen bond formation, principle component analysis, and free energy landscape calculations for NA1 bound protein displayed stable complex formation in 100 ns molecular dynamics simulation, compared to unbound macro domain and natural substrate adenosine-5-diphosphoribose bound macro domain that served as a positive control. The molecular mechanics Poisson-Boltzmann surface area analysis of NA1 demonstrated binding free energy of -175.978 ± 0.401 kJ/mol in comparison to natural substrate which had binding free energy of -133.403 ± 14.103 kJ/mol. In silico analysis by modelling tool ADMET and prediction of biological activity of these compounds further validated them as putative therapeutic molecules against SARS-CoV-2. Taken together, this study offers NA1 as a lead SARS-CoV-2 A1pp domain inhibitor for future testing and development as therapeutics against human coronavirus.
Keywords: A1pp domain; FDA approved Drugs; In silico; Macro domain; Nucleoside analogues; SARS-CoV-2.
【저자키워드】 in silico, SARS-CoV-2., A1pp domain, FDA approved Drugs, Macro domain, Nucleoside analogues, 【초록키워드】 SARS-CoV-2, viral infection, coronavirus, Pathogenesis, Therapeutics, molecular dynamics, FDA, binding free energy, FDA approved drug, binding affinity, Molecular dynamics simulation, free energy, Human coronavirus, Protein, intestine, free energy landscape, respiratory tract, molecular, crystal structure, inhibitor, adenosine, binding, Molecular mechanics, Hydrogen bond, RMSD, RMSF, FDA approved Drugs, Nucleoside analogues, nucleoside analogue, Interaction, Analysis, hydrogen, surface area, phosphatase, Therapeutic molecule, nadide, these viruses, docking scores, domain, adenosine diphosphate, nucleoside, hydrophobic, these compounds, positive control, solvent, ribose, gyration, radius of gyration, radius, macro, offer, deviation, biological activity, infect, Host, FIVE, fluctuation, substrate binding site, stable complex, citicholine, root mean square deviation, root mean square fluctuation, performed, conserved, reported, inhibit, approved, exhibited, demonstrated, analysis, these compound, promote, These viruses, 【제목키워드】 SARS-CoV-2, FDA approved drug, nucleoside analogue, identification, domain,