tetano
Editor, Senior Moderator
J Biomol Struct Dyn
. 2020 May 28;1-16.
doi: 10.1080/07391102.2020.1775127. Online ahead of print.
Identification of Potential Inhibitors of SARS-COV-2 Endoribonuclease (EndoU) From FDA Approved Drugs: A Drug Repurposing Approach to Find Therapeutics for COID19
Anshuman Chandra[SUP] 1 [/SUP], Vaishali Gurjar[SUP] 2 [/SUP], Imteyaz Qamar[SUP] 1 [/SUP], Nagendra Singh[SUP] 1 [/SUP]
Affiliations
Abstract
SARS-CoV-2 is causative agent of COVID 19, which is responsible for severe social and economic disruption globally. Lack of vaccine or antiviral drug with clinical efficacy suggested that drug repurposing approach may provide a quick therapeutic solution to COVID19. Nonstructural Protein-15 (NSP15) encodes for an uridylate-specific endoribonuclease (EndoU) enzyme, essential for virus life cycle and an attractive target for drug development. We have performed in silico based virtual screening of FDA approved compounds targeting EndoU in search of COVID19 drugs from commercially available approved molecules. Two drugs Glisoxepide and Idarubicin used for treatment for diabetes and leukemia respectively were selected as stronger binder of EndoU. Both the drugs bound to the active site of the viral endonuclease by forming attractive intermolecular interactions with catalytically essential amino acid residues, His235, His250 and Lys290. Molecular dynamics simulation studies showed stable conformation dynamics upon drugs binding to endoU. The binding free energies for Glisoxepide and Idarubicin were calculated to be -141 ? 11 and -136 ? 16 kJ/mol respectively. The IC[SUB]50[/SUB] were predicted to be 9.2?M and 30?M for Glisoxepide and Idarubicin respectively. Comparative structural analysis showed the stronger binding of EndoU to Glisoxepide and Idarubicin than uridine monophosphate (UMP). Surface area calculations showed buried are of 361.8?[SUP]2[/SUP] by Glisoxepide which is almost double of the area occupied by UMP suggesting stronger binding of the drug than the ribonucleotide. However, further studies on these drugs for evaluation of their clinical efficacy and dose formulations may be required, which may provide a quick therapeutic option to treat COVID-19.Abbreviation: COVID-19: Coronavirus Disease 2019; PCA: Principal Component Analysis; MD: Molecular Dynamics; MM/PBSA: Molecular Mechanics Poisson-Boltzmann Surface Area; nCoV: Novel Coronavirus; PME: Particle-Mesh Ewald; RMSD: Root Mean Square Deviations; RMSF: Root Mean Square Fluctuations; SARS-CoV-2: Severe Acute Respiratory Syndrome-Coronavirus-2; SASA: Solvent Accessible Surface Area; SPC: Simple Point Charge.
Keywords: Binding Affinity; Drug Repurposing; Endonuclease; IC50; Molecular Dynamic Simulation; SARS-CoV-2.
. 2020 May 28;1-16.
doi: 10.1080/07391102.2020.1775127. Online ahead of print.
Identification of Potential Inhibitors of SARS-COV-2 Endoribonuclease (EndoU) From FDA Approved Drugs: A Drug Repurposing Approach to Find Therapeutics for COID19
Anshuman Chandra[SUP] 1 [/SUP], Vaishali Gurjar[SUP] 2 [/SUP], Imteyaz Qamar[SUP] 1 [/SUP], Nagendra Singh[SUP] 1 [/SUP]
Affiliations
- PMID: 32462970
- DOI: 10.1080/07391102.2020.1775127
Abstract
SARS-CoV-2 is causative agent of COVID 19, which is responsible for severe social and economic disruption globally. Lack of vaccine or antiviral drug with clinical efficacy suggested that drug repurposing approach may provide a quick therapeutic solution to COVID19. Nonstructural Protein-15 (NSP15) encodes for an uridylate-specific endoribonuclease (EndoU) enzyme, essential for virus life cycle and an attractive target for drug development. We have performed in silico based virtual screening of FDA approved compounds targeting EndoU in search of COVID19 drugs from commercially available approved molecules. Two drugs Glisoxepide and Idarubicin used for treatment for diabetes and leukemia respectively were selected as stronger binder of EndoU. Both the drugs bound to the active site of the viral endonuclease by forming attractive intermolecular interactions with catalytically essential amino acid residues, His235, His250 and Lys290. Molecular dynamics simulation studies showed stable conformation dynamics upon drugs binding to endoU. The binding free energies for Glisoxepide and Idarubicin were calculated to be -141 ? 11 and -136 ? 16 kJ/mol respectively. The IC[SUB]50[/SUB] were predicted to be 9.2?M and 30?M for Glisoxepide and Idarubicin respectively. Comparative structural analysis showed the stronger binding of EndoU to Glisoxepide and Idarubicin than uridine monophosphate (UMP). Surface area calculations showed buried are of 361.8?[SUP]2[/SUP] by Glisoxepide which is almost double of the area occupied by UMP suggesting stronger binding of the drug than the ribonucleotide. However, further studies on these drugs for evaluation of their clinical efficacy and dose formulations may be required, which may provide a quick therapeutic option to treat COVID-19.Abbreviation: COVID-19: Coronavirus Disease 2019; PCA: Principal Component Analysis; MD: Molecular Dynamics; MM/PBSA: Molecular Mechanics Poisson-Boltzmann Surface Area; nCoV: Novel Coronavirus; PME: Particle-Mesh Ewald; RMSD: Root Mean Square Deviations; RMSF: Root Mean Square Fluctuations; SARS-CoV-2: Severe Acute Respiratory Syndrome-Coronavirus-2; SASA: Solvent Accessible Surface Area; SPC: Simple Point Charge.
Keywords: Binding Affinity; Drug Repurposing; Endonuclease; IC50; Molecular Dynamic Simulation; SARS-CoV-2.