tetano
Editor, Senior Moderator
ACS Med Chem Lett. 2014 Jan 9;5(1):61-64.
Computation-guided discovery of influenza endonuclease inhibitors.
Chen E1, Swift RV1, Alderson N2, Feher VA1, Feng GS2, Amaro RE1.
Author information
Abstract
Influenza is a global human health threat, and there is an immediate need for new antiviral therapies to circumvent the limitations of vaccination and current small molecule therapies. During viral transcription, influenza incorporates the 5'-end of the host cell's mRNA in a process that requires the influenza endonuclease. Based on recently published endonuclease crystalized structures, a three-dimensional pharmacophore was developed and used to virtually screen 450,000 compounds for influenza endonuclease inhibitors. Of 264 compounds tested in a FRET-based endonuclease-inhibition assay, 16 inhibitors (IC50 <50 μM) that span 5 molecular classes novel to this endonuclease were found (6.1% hit rate). To determine cytotoxicity and antiviral activity, subsequent cellular assays were performed. Two compounds suppress viral replication with negligible cell toxicity.
KEYWORDS:
Antiviral, endonuclease, influenza A, pharmacophore, virtual screening
PMID:
24490002
[PubMed]
http://www.ncbi.nlm.nih.gov/pubmed/24490002
Computation-guided discovery of influenza endonuclease inhibitors.
Chen E1, Swift RV1, Alderson N2, Feher VA1, Feng GS2, Amaro RE1.
Author information
Abstract
Influenza is a global human health threat, and there is an immediate need for new antiviral therapies to circumvent the limitations of vaccination and current small molecule therapies. During viral transcription, influenza incorporates the 5'-end of the host cell's mRNA in a process that requires the influenza endonuclease. Based on recently published endonuclease crystalized structures, a three-dimensional pharmacophore was developed and used to virtually screen 450,000 compounds for influenza endonuclease inhibitors. Of 264 compounds tested in a FRET-based endonuclease-inhibition assay, 16 inhibitors (IC50 <50 μM) that span 5 molecular classes novel to this endonuclease were found (6.1% hit rate). To determine cytotoxicity and antiviral activity, subsequent cellular assays were performed. Two compounds suppress viral replication with negligible cell toxicity.
KEYWORDS:
Antiviral, endonuclease, influenza A, pharmacophore, virtual screening
PMID:
24490002
[PubMed]
http://www.ncbi.nlm.nih.gov/pubmed/24490002