4YD0

Influenza polymerase basic protein 2 (PB2) bound to an azaindole-tetrazole inhibitor

Summary for 4YD0

• Entry DOI: 10.2210/pdb4yd0/pdb
• Descriptor: Polymerase basic protein 2, 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-[(1R,2S,3S,4R)-3-(1H-tetrazol-5-yl)bicyclo[2.2.2]oct-2-yl]pyrimidin-4-amine (3 entities in total)
• Functional Keywords: small-molecule drug, inhibitor, flu, m7-gtp pocket, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Influenza A virus
• Cellular location: Virion: Q30NP1
• Total number of polymer chains: 1
• Total formula weight: 19614.20

Authors

Jacobs, M.D. (deposition date: 2015-02-20, release date: 2015-04-15, Last modification date: 2024-02-28)

Primary citation

Boyd, M.J.,Bandarage, U.K.,Bennett, H.,Byrn, R.R.,Davies, I.,Gu, W.,Jacobs, M.,Ledeboer, M.W.,Ledford, B.,Leeman, J.R.,Perola, E.,Wang, T.,Bennani, Y.,Clark, M.P.,Charifson, P.S.
Isosteric replacements of the carboxylic acid of drug candidate VX-787: Effect of charge on antiviral potency and kinase activity of azaindole-based influenza PB2 inhibitors.
Bioorg.Med.Chem.Lett., 25:1990-1994, 2015

PubMed Abstract: VX-787 is a first in class, orally bioavailable compound that offers unparalleled potential for the treatment of pandemic and seasonal influenza. As a part of our routine SAR exploration, carboxylic acid isosteres of VX-787 were prepared and tested against influenza A. It was found that the negative charge is important for maintaining potency and selectivity relative to kinase targets. Neutral carboxylic acid replacements generally resulted in compounds that were significantly less potent and less selective relative to the charged species.

PubMed: 25827523
DOI: 10.1016/j.bmcl.2015.03.013

Experimental method

X-RAY DIFFRACTION (2.62 Å)