Identification of potential inhibitors of SARS-COV-2 endoribonuclease (EndoU) from FDA approved drugs: a drug repurposing approach to find therapeutics for COVID-19

Anshuman Chandra,Vaishali Gurjar,Imteyaz Qamar,Nagendra Singh

10.1080/07391102.2020.1775127

Research curated

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 COVID-19. 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 COVID-19 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 IC50 were predicted to be 9.2 µM and 30 µM for Glisoxepide and Idarubicin, respectively. Comparative structural analysis showed the stronger binding of EndoU to Glisoxepide and Idarubicin than to uridine monophosphate (UMP). Surface area calculations showed buried are of 361.8Å2 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.

Source: PMC

Related molecules

Name	Synonyms	Genes
Uridylate-specific endoribonuclease	NSP15, Non-structural protein 15, Nonstructural protein 15, NendoU, endoRNAse	rep, ORF1a-1b
Glisoxepide
Idarubicin
Tasosartan
Ergotamine
Dihydroergotamine

Related interactions

Target	Drug	Type	Result
Uridylate-specific endoribonuclease	Glisoxepide	Computational	positive
Uridylate-specific endoribonuclease	Idarubicin	Computational	positive
Uridylate-specific endoribonuclease	Tasosartan	Computational	positive
Uridylate-specific endoribonuclease	Dihydroergotamine	Computational	positive
Uridylate-specific endoribonuclease	Ergotamine	Computational	positive