Ensemble-based virtual screening reveals potential novel antiviral compounds for avian influenza neuraminidase.
Avian influenza virus subtype H5N1 is a potential pandemic threat with human-adapted strains resistant to antiviral drugs. Although virtual screening (VS) against a crystal or relaxed receptor structure is an established method to identify potential inhibitors, the more dynamic changes within binding sites are neglected. To accommodate full receptor flexibility, we use AutoDock4 to screen the NCI diversity set against representative receptor ensembles extracted from explicitly solvated molecular dynamics simulations of the neuraminidase system. The top hits are redocked to the entire nonredundant receptor ensemble and rescored using the relaxed complex scheme (RCS). Of the 27 top hits reported, half ranked very poorly if only crystal structures are used. These compounds target the catalytic cavity as well as the newly identified 150- and 430-cavities, which exhibit dynamic properties in electrostatic surface and geometric shape. This ensemble-based VS and RCS approach may offer improvement over existing strategies for structure-based drug discovery.
Cheng
Lily S
LS
National Biomedical Computation Resource, University of California, San Diego, La Jolla, California 92093, USA.
Amaro
Rommie E
RE
Xu
Dong
D
Li
Wilfred W
WW
Arzberger
Peter W
PW
McCammon
J Andrew
JA
D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects* / Q000201:enzymology; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D012997:Solvents; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013499:Surface Properties
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D012997:Solvents; D009439:Neuraminidase