4TWY

Structure of SARS-3CL protease complex with a phenylbenzoyl (S,R)-N-decalin type inhibitor

Summary for 4TWY

• Entry DOI: 10.2210/pdb4twy/pdb
• Related: 4TWW 4TWY
• Descriptor: 3C-like proteinase, (2S)-2-({[(3S,4aR,8aS)-2-(biphenyl-4-ylcarbonyl)decahydroisoquinolin-3-yl]methyl}amino)-3-(1H-imidazol-5-yl)propanal (3 entities in total)
• Functional Keywords: hydrase proteinase converting, designed inhibitor, hydrase-inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human SARS coronavirus (SARS-CoV)
• Total number of polymer chains: 1
• Total formula weight: 34303.21

Authors

Akaji, K.,Teruya, K.,Shimamoto, Y.,Sanjho, A.,Yamashita, E.,Nakagawa, A. (deposition date: 2014-07-02, release date: 2015-02-18, Last modification date: 2024-11-20)

Primary citation

Shimamoto, Y.,Hattori, Y.,Kobayashi, K.,Teruya, K.,Sanjoh, A.,Nakagawa, A.,Yamashita, E.,Akaji, K.
Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors
Bioorg.Med.Chem., 23:876-890, 2015

PubMed Abstract: The design and evaluation of a novel decahydroisoquinolin scaffold as an inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CL(pro)) are described. Focusing on hydrophobic interactions at the S2 site, the decahydroisoquinolin scaffold was designed by connecting the P2 site cyclohexyl group of the substrate-based inhibitor to the main-chain at the α-nitrogen atom of the P2 position via a methylene linker. Starting from a cyclohexene enantiomer obtained by salt resolution, trans-decahydroisoquinolin derivatives were synthesized. All decahydroisoquinolin inhibitors synthesized showed moderate but clear inhibitory activities for SARS 3CL(pro), which confirmed the fused ring structure of the decahydroisoquinolin functions as a novel scaffold for SARS 3CL(pro) inhibitor. X-ray crystallographic analyses of the SARS 3CL(pro) in a complex with the decahydroisoquinolin inhibitor revealed the expected interactions at the S1 and S2 sites, as well as additional interactions at the N-substituent of the inhibitor.

PubMed: 25614110
DOI: 10.1016/j.bmc.2014.12.028

Experimental method

X-RAY DIFFRACTION (1.6 Å)