Identification of FDA approved drugs and nucleoside analogues as potential SARS-CoV-2 A1pp domain inhibitor: An in silico study

• Published in: Computers in biology and medicine 2021-03, Vol.130, p.104185-104185, Article 104185
• Main Authors: Singh, Atul Kumar, Kushwaha, Prem Prakash, Prajapati, Kumari Sunita, Shuaib, Mohd, Gupta, Sanjay, Kumar, Shashank
• Format: Article
• Language: English
• Subjects: A1pp domain; Adenosine; Adenosine diphosphate; Antiviral Agents - chemistry; Antiviral Agents - therapeutic use; Binding energy; Binding Sites; Biological activity; Complex formation; Coronavirus Papain-Like Proteases - antagonists & inhibitors; Coronavirus Papain-Like Proteases - chemistry; Coronaviruses; COVID-19; COVID-19 - drug therapy; Crystal structure; Domains; Drug Approval; Drug development; Drug screening; Drugs; Energy; FDA approval; FDA approved Drugs; Free energy; Genomes; Humans; Hydrogen bonding; Hydrogen bonds; Hydrophobicity; In silico; Infections; Inhibitors; Intestine; Kinases; Lead compounds; Ligands; Macro domain; Molecular Docking Simulation; Molecular dynamics; NAD; Nucleoside analogs; Nucleoside analogues; Nucleosides; Nucleosides - chemistry; Nucleosides - therapeutic use; Pathogenesis; Pharmacokinetics; Phosphatase; Principal components analysis; Protein Binding; Proteins; Respiratory tract; Respiratory tract diseases; Ribose; Ribosylation; SARS-CoV-2; SARS-CoV-2 - chemistry; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Simulation; Substrates; United States; United States Food and Drug Administration; Viral diseases; Viral infections; Viruses
• ISSN: 0010-4825; 1879-0534
• DOI: 10.1016/j.compbiomed.2020.104185

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. •SARS-CoV-2 ADP-Ribose phosphatase is a drugable target.•FDA approved drugs act as potential inhibitors of ADP-Ribose phosphatase.•Nucleoside inhibitor binds and stabilizes the ADP-Ribose phosphatase.