6W5H

1.85 A resolution structure of Norovirus 3CL protease in complex with inhibitor 5d

Summary for 6W5H

• Entry DOI: 10.2210/pdb6w5h/pdb
• Related PRD ID: PRD_002452
• Descriptor: 3C-LIKE PROTEASE, 2-(3-chlorophenyl)-2-methylpropyl [(2S)-3-cyclohexyl-1-({(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)-1-oxopropan-2-yl]carbamate (3 entities in total)
• Functional Keywords: protease, norovirus 3cl protease, inhhibitors, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Norwalk virus (strain GI/Human/United States/Norwalk/1968) (Hu/NV/NV/1968/US)
• Total number of polymer chains: 4
• Total formula weight: 82068.04

Authors

Lovell, S.,Kashipathy, M.M.,Battaile, K.P.,Rathnayake, A.D.,Kim, Y.,Chang, K.O.,Groutas, W.C. (deposition date: 2020-03-13, release date: 2020-09-30, Last modification date: 2024-10-23)

Primary citation

Rathnayake, A.D.,Kim, Y.,Dampalla, C.S.,Nguyen, H.N.,Jesri, A.M.,Kashipathy, M.M.,Lushington, G.H.,Battaile, K.P.,Lovell, S.,Chang, K.O.,Groutas, W.C.
Structure-Guided Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease.
J.Med.Chem., 63:11945-11963, 2020

PubMed Abstract: Acute gastroenteritis caused by noroviruses has a major impact on public health worldwide in terms of morbidity, mortality, and economic burden. The disease impacts most severely immunocompromised patients, the elderly, and children. The current lack of approved vaccines and small-molecule therapeutics for the treatment and prophylaxis of norovirus infections underscores the need for the development of norovirus-specific drugs. The studies described herein entail the use of the -dimethyl moiety as a means of improving the pharmacological activity and physicochemical properties of a dipeptidyl series of transition state inhibitors of norovirus 3CL protease, an enzyme essential for viral replication. Several compounds were found to be potent inhibitors of the enzyme in biochemical and cell-based assays. The pharmacological activity and cellular permeability of the inhibitors were found to be sensitive to the location of the -dimethyl group.

PubMed: 32945669
DOI: 10.1021/acs.jmedchem.0c01252

Experimental method

X-RAY DIFFRACTION (1.85 Å)