Paper Citing NAMD - Abstract
Yanagita, Hiroshi; Yamamoto, Norio; Fuji, Hideyoshi; Liu, Xinli; Ogata, Masakazu; Yokota, Mizuho; Takaku, Hiroshi; Hasegawa, Hideki; Odagiri, Takato; Tashiro, Masato; Hoshino, Tyuji
Mechanism of Drug Resistance of Hemagglutinin of Influenza Virus and Potent Scaffolds Inhibiting Its Function
ACS CHEMICAL BIOLOGY, 7:552-562, MAR 2012
Highly pathogenic influenza viruses have become a global threat to humans. It is important to select an affective therapeutic option suitable for the subtypes in an epidemics or pandemic. To increase the options, the development of novel antiviral agents acting on targets different from those of the currently approved drugs is required. In this study. we performed molecular dynamics simulations on a spike protein on the viral envelop, hemagglutinin for the wild type and three kinds of mutants using a model system consisting of a trimeric hemagglutin complex, viral lipid membrane. solvation waters, and ions . A natural product stachyflin, which shows a high level of antiviral activity specific to some subtypes of influenza viruses, was examined on binding to the wild-type hemagglutinin was clarified. Next, 8 compounds were selected from a chemical database by in silico screening, considering the findings from the simulations. Inhibitory activities to suppress the proliferation of influenza virus were measured by cell-based antiviral assays, and chemical scaffolds were found to be potent for an inhibitor. More than 30 derivatives bearing either of these two chemical scaffolds were synthesized, and cell culture assays were carried out of evaluate the compound potency. Several derivatives displayed a high compound potency, and 50% effective concentrations of two synthesized compounds were below 1 mu M
