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Novel Druggable Hot Spots in Avian Influenza Neuraminidase H5N1 Revealed by Computational Solvent Mapping of a Reduced and Representative Receptor Ensemble
Author(s) -
Landon Melissa R.,
Amaro Rommie E.,
Baron Riccardo,
Ngan Chi Ho,
Ozonoff David,
Andrew McCammon J.,
Vajda Sandor
Publication year - 2008
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2007.00614.x
Subject(s) - neuraminidase , influenza a virus subtype h5n1 , hot spot (computer programming) , druggability , molecular dynamics , chemistry , binding site , neuraminidase inhibitor , influenza a virus , computational biology , biology , biochemistry , virology , virus , covid-19 , gene , computational chemistry , medicine , computer science , disease , pathology , infectious disease (medical specialty) , operating system
The influenza virus subtype H5N1 has raised concerns of a possible human pandemic threat because of its high virulence and mutation rate. Although several approved anti‐influenza drugs effectively target the neuraminidase, some strains have already acquired resistance to the currently available anti‐influenza drugs. In this study, we present the synergistic application of extended explicit solvent molecular dynamics (MD) and computational solvent mapping (CS‐Map) to identify putative ‘hot spots’ within flexible binding regions of N1 neuraminidase. Using representative conformations of the N1 binding region extracted from a clustering analysis of four concatenated 40‐ns MD simulations, CS‐Map was utilized to assess the ability of small, solvent‐sized molecules to bind within close proximity to the sialic acid binding region. Mapping analyses of the dominant MD conformations reveal the presence of additional hot spot regions in the 150‐ and 430‐loop regions. Our hot spot analysis provides further support for the feasibility of developing high‐affinity inhibitors capable of binding these regions, which appear to be unique to the N1 strain.