4PIS

Crystal structure of human adenovirus 8 protease in complex with a nitrile inhibitor

Summary for 4PIS

• Entry DOI: 10.2210/pdb4pis/pdb
• Related: 4PIE 4PIQ
• Descriptor: Protease, PVI, N~2~-[(2R)-2-(3,5-dichlorophenyl)-2-(dimethylamino)acetyl]-N-({2-[(Z)-iminomethyl]pyrimidin-4-yl}methyl)-L-isoleucinamide, ... (4 entities in total)
• Functional Keywords: adenain, cysteine protease, pvic, cofactor, nitrile inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human adenovirus 8 (HAdV-8); More
• Total number of polymer chains: 2
• Total formula weight: 24843.41

Authors

Mac Sweeney, A.,Grosche, P.,Ellis, D.,Combrink, K.,Erbel, P.,Hughes, N.,Sirockin, F.,Melkko, S.,Bernardi, A.,Ramage, P.,Jarousse, N.,Altmann, E. (deposition date: 2014-05-09, release date: 2014-09-10, Last modification date: 2024-10-30)

Primary citation

Mac Sweeney, A.,Grosche, P.,Ellis, D.,Combrink, K.,Erbel, P.,Hughes, N.,Sirockin, F.,Melkko, S.,Bernardi, A.,Ramage, P.,Jarousse, N.,Altmann, E.
Discovery and structure-based optimization of adenain inhibitors.
Acs Med.Chem.Lett., 5:937-941, 2014

PubMed Abstract: The cysteine protease adenain is the essential protease of adenovirus and, as such, represents a promising target for the treatment of ocular and other adenoviral infections. Through a concise two-pronged hit discovery approach we identified tetrapeptide nitrile 1 and pyrimidine nitrile 2 as complementary starting points for adenain inhibition. These hits enabled the first high-resolution X-ray cocrystal structures of adenain with inhibitors bound and revealed the binding mode of 1 and 2. The screening hits were optimized by a structure-guided medicinal chemistry strategy into low nanomolar drug-like inhibitors of adenain.

PubMed: 25147618
DOI: 10.1021/ml500224t

Experimental method

X-RAY DIFFRACTION (2.1 Å)