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

dc.contributor.authorSingh, Atul Kumar
dc.contributor.authorKushwaha, Prem Prakash
dc.contributor.authorPrajapati, Kumari Sunita
dc.contributor.authorShuaib, Mohd
dc.contributor.authorGupta, Sanjay
dc.contributor.authorKumar, Shashank
dc.date.accessioned2024-01-16T14:23:05Z
dc.date.accessioned2024-08-13T10:34:56Z
dc.date.available2024-01-16T14:23:05Z
dc.date.available2024-08-13T10:34:56Z
dc.date.issued2020-12-19T00:00:00
dc.description.abstractCoronaviruses 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. � 2020en_US
dc.identifier.doi10.1016/j.compbiomed.2020.104185
dc.identifier.issn104825
dc.identifier.urihttps://doi.org/10.1016/j.compbiomed.2020.104185
dc.identifier.urihttps://kr.cup.edu.in/handle/32116/2836
dc.language.isoen_USen_US
dc.publisherElsevier Ltden_US
dc.subjectA1pp domainen_US
dc.subjectFDA approved Drugsen_US
dc.subjectIn silicoen_US
dc.subjectMacro domainen_US
dc.subjectNucleoside analoguesen_US
dc.subjectSARS-CoV-2en_US
dc.titleIdentification of FDA approved drugs and nucleoside analogues as potential SARS-CoV-2 A1pp domain inhibitor: An in silico studyen_US
dc.title.journalComputers in Biology and Medicineen_US
dc.typeArticleen_US
dc.type.accesstypeOpen Accessen_US

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