5CUQ

Identification and characterization of novel broad spectrum inhibitors of the flavivirus methyltransferase

Summary for 5CUQ

• Entry DOI: 10.2210/pdb5cuq/pdb
• Descriptor: Nonstructural protein NS5, N,N'-BIS(4-AMINO-2-METHYLQUINOLIN-6-YL)UREA (3 entities in total)
• Functional Keywords: inhibitor, complex, dengue virus, methyltransferase, viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Dengue virus 3
• Total number of polymer chains: 2
• Total formula weight: 60884.02

Authors

Brecher, B.,Chen, H.,Li, Z.,Banavali, N.K.,Jones, S.A.,Zhang, J.,Kramer, L.D.,Li, H.M. (deposition date: 2015-07-24, release date: 2016-02-03, Last modification date: 2023-09-27)

Primary citation

Brecher, M.,Chen, H.,Li, Z.,Banavali, N.K.,Jones, S.A.,Zhang, J.,Kramer, L.D.,Li, H.
Identification and Characterization of Novel Broad-Spectrum Inhibitors of the Flavivirus Methyltransferase.
Acs Infect Dis., 1:340-349, 2015

PubMed Abstract: Flavivirus methyltransferase (MTase) is essential for viral replication. Here we report the identification of small molecules through virtual screening that putatively bind to the SAM-binding site of flavivirus MTase and inhibit its function. Six of these computationally predicted binders were identified to show significant MTase inhibition with low micromolar inhibitory activity. The most active compounds showed broad-spectrum activity against the MTase proteins of other flaviviruses. Two of these compounds also showed low cytotoxicity and high antiviral efficacy in cell-based assays. Competitive binding analyses indicated that the inhibitors performed their inhibitory function through competitive binding to the SAM cofactor binding site of the MTase. The crystal structure of the MTase-inhibitor complex further supports the mode of action and provides routes for their further optimization as flavivirus MTase inhibitors.

PubMed: 26726314
DOI: 10.1021/acsinfecdis.5b00070

Experimental method

X-RAY DIFFRACTION (1.696 Å)