Plasticity of the 340-Loop in Influenza Neuraminidase Offers New Insight for Antiviral Drug Development.
Int J Mol Sci
; 21(16)2020 Aug 06.
Article
in English
| MEDLINE | ID: covidwho-1934101
ABSTRACT
The recently discovered 340-cavity in influenza neuraminidase (NA) N6 and N7 subtypes has introduced new possibilities for rational structure-based drug design. However, the plasticity of the 340-loop (residues 342-347) and the role of the 340-loop in NA activity and substrate binding have not been deeply exploited. Here, we investigate the mechanism of 340-cavity formation and demonstrate for the first time that seven of nine NA subtypes are able to adopt an open 340-cavity over 1.8 µs total molecular dynamics simulation time. The finding that the 340-loop plays a role in the sialic acid binding pathway suggests that the 340-cavity can function as a druggable pocket. Comparing the open and closed conformations of the 340-loop, the side chain orientation of residue 344 was found to govern the formation of the 340-cavity. Additionally, the conserved calcium ion was found to substantially influence the stability of the 340-loop. Our study provides dynamical evidence supporting the 340-cavity as a druggable hotspot at the atomic level and offers new structural insight in designing antiviral drugs.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Antiviral Agents
/
Orthomyxoviridae
/
Drug Development
/
Neuraminidase
Type of study:
Prognostic study
Language:
English
Year:
2020
Document Type:
Article
Affiliation country:
Ijms21165655
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