6E0Q

The N-terminal domain of PA endonuclease from the influenza H1N1 virus in complex with 4,6-dihydroxy-2-methyl-5-oxocyclohepta-1,3,6-triene-1-carboxylic acid

Summary for 6E0Q

• Entry DOI: 10.2210/pdb6e0q/pdb
• Descriptor: Polymerase acidic protein, MANGANESE (II) ION, 4,6-dihydroxy-2-methyl-5-oxocyclohepta-1,3,6-triene-1-carboxylic acid, ... (5 entities in total)
• Functional Keywords: inhibitor, endonuclease, influenza, pa domain, hydrolase-hydrolase inhibitor complex, viral protein, hydrolase/hydrolase inhibitor
• Biological source: Influenza A virus
• Total number of polymer chains: 1
• Total formula weight: 22898.83

Authors

Dick, B.L.,Morrison, C.N.,Cohen, S.M. (deposition date: 2018-07-06, release date: 2018-11-07, Last modification date: 2023-10-11)

Primary citation

Credille, C.V.,Dick, B.L.,Morrison, C.N.,Stokes, R.W.,Adamek, R.N.,Wu, N.C.,Wilson, I.A.,Cohen, S.M.
Structure-Activity Relationships in Metal-Binding Pharmacophores for Influenza Endonuclease.
J. Med. Chem., 61:10206-10217, 2018

PubMed Abstract: Metalloenzymes represent an important target space for drug discovery. A limitation to the early development of metalloenzyme inhibitors has been the lack of established structure-activity relationships (SARs) for molecules that bind the metal ion cofactor(s) of a metalloenzyme. Herein, we employed a bioinorganic perspective to develop an SAR for inhibition of the metalloenzyme influenza RNA polymerase PA endonuclease. The identified trends highlight the importance of the electronics of the metal-binding pharmacophore (MBP), in addition to MBP sterics, for achieving improved inhibition and selectivity. By optimization of the MBPs for PA endonuclease, a class of highly active and selective fragments was developed that displays IC values <50 nM. This SAR led to structurally distinct molecules that also displayed IC values of ∼10 nM, illustrating the utility of a metal-centric development campaign in generating highly active and selective metalloenzyme inhibitors.

PubMed: 30351002
DOI: 10.1021/acs.jmedchem.8b01363

Experimental method

X-RAY DIFFRACTION (2.35 Å)