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New polycyclic dual inhibitors of the wild type and the V27A mutant M2 channel of the influenza A virus with unexpected binding mode

Posted May 6th, 2015 by sruiz
TitleNew polycyclic dual inhibitors of the wild type and the V27A mutant M2 channel of the influenza A virus with unexpected binding mode
Publication TypeJournal Article
Year of Publication2015
AuthorsRey-Carrizo, M, Gazzarrini S, Llabrés S, Frigolé-Vivas M, Juárez-Jiménez J, Font-Bardia M, Naesens L, Moroni A, Luque JF, Vázquez S
JournalEuropean Journal of Medicinal Chemistry
Volume96
Pagination318 - 329
ISSN0223-5234
KeywordsMolecular dynamics
AbstractTwo new polycyclic scaffolds were synthesized and evaluated as anti-influenza A compounds. The 5-azapentacyclo[6.4.0.02,10.03,7.09,11]dodecane derivatives were only active against the wild-type M2 channel in the low-micromolar range. However, some of the 14-azaheptacyclo[8.6.1.02,5.03,11.04,9.06,17.012,16]heptadecane derivatives were dual inhibitors of the wild-type and the V27A mutant M2 channels. The antiviral activity of these molecules was confirmed by cell culture assays. Their binding mode was analysed through molecular dynamics simulations, which showed the existence of distinct binding modes in the wild type M2 channel and its V27A variant.
URLhttp://www.sciencedirect.com/science/article/pii/S0223523415002895
DOIhttp://dx.doi.org/10.1016/j.ejmech.2015.04.030