Ensemble-based virtual screening reveals potential novel antiviral compounds for avian influenza neuraminidase

被引:180
作者
Cheng, Lily S. [2 ]
Amaro, Romanic E. [1 ,3 ]
Xu, Dong [2 ]
Li, Wilfred W. [2 ]
Arzberger, Peter W. [2 ]
McCammon, J. Andrew [1 ,2 ,3 ,4 ,5 ]
机构
[1] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Natl Biomed Computat Resource, La Jolla, CA 92093 USA
[3] Univ Calif San Diego, NSF Ctr Theoret Biol Phys, La Jolla, CA 92093 USA
[4] Univ Calif San Diego, Howard Hughes Med Inst, La Jolla, CA 92093 USA
[5] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA
关键词
D O I
10.1021/jm8001197
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:3878 / 3894
页数:17
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