5DG6

2.35A resolution structure of Norovirus 3CL protease in complex an oxadiazole-based, cell permeable macrocyclic (21-mer) inhibitor

Summary for 5DG6

• Entry DOI: 10.2210/pdb5dg6/pdb
• Related: 5DGJ
• Related PRD ID: PRD_002187
• Descriptor: 3C-LIKE PROTEASE, CHLORIDE ION, tert-butyl [(4S,7S,10S)-7-(cyclohexylmethyl)-10-(hydroxymethyl)-5,8,13-trioxo-23-oxa-6,9,14,21,22-pentaazabicyclo[18.2.1]tricosa-1(22),20-dien-4-yl]carbamate, ... (4 entities in total)
• Functional Keywords: protease, norovirus, norwalk virus, antiviral inhibitors, oxadiazole inhibitor, cell permeable, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Norwalk virus (Hu/NV/NV/1968/US)
• Total number of polymer chains: 2
• Total formula weight: 40965.38

Authors

Lovell, S.,Battaile, K.P.,Mehzabeen, N.,Damalanka, V.C.,Kim, Y.,Alliston, K.R.,Weerawarna, P.M.,Kankanamalage, A.C.G.,Lushington, G.H.,Chang, K.-O.,Groutas, W.C. (deposition date: 2015-08-27, release date: 2016-02-10, Last modification date: 2023-09-27)

Primary citation

Damalanka, V.C.,Kim, Y.,Alliston, K.R.,Weerawarna, P.M.,Galasiti Kankanamalage, A.C.,Lushington, G.H.,Mehzabeen, N.,Battaile, K.P.,Lovell, S.,Chang, K.O.,Groutas, W.C.
Oxadiazole-Based Cell Permeable Macrocyclic Transition State Inhibitors of Norovirus 3CL Protease.
J.Med.Chem., 59:1899-1913, 2016

PubMed Abstract: Human noroviruses are the primary causative agents of acute gastroenteritis and a pressing public health burden worldwide. There are currently no vaccines or small molecule therapeutics available for the treatment or prophylaxis of norovirus infections. Norovirus 3CL protease plays a vital role in viral replication by generating structural and nonstructural proteins via the cleavage of the viral polyprotein. Thus, molecules that inhibit the viral protease may have potential therapeutic value. We describe herein the structure-based design, synthesis, and in vitro and cell-based evaluation of the first class of oxadiazole-based, permeable macrocyclic inhibitors of norovirus 3CL protease.

PubMed: 26823007
DOI: 10.1021/acs.jmedchem.5b01464

Experimental method

X-RAY DIFFRACTION (2.35 Å)