More than two dozen promising and novel compounds have been isolated from which new "designer drugs" might be developed to combat "bird flu," according to a new study.
In some cases, the compounds appeared to be equal or stronger inhibitors than currently available anti-flu remedies, said the study conducted by a team of scientists with the University of California, San Diego (UCSD).
As the specter of a worldwide outbreak of avian or "bird flu" lingers, health officials recognize that new drugs are desperately needed since some strains of the virus already have developed resistance to the current roster of anti-flu remedies, the study said.
"If those resistant strains begin to propagate, then that's when we're going to be in trouble, because we don't have any anti-virals active against them," said Rommie Amaro, a postdoctoral fellow in chemistry at UCSD. "So, we should have something as a backup, and that's exactly why we're working on this."
"In light of the urgency to find drugs to combat this virus, we're hopeful that our results will assist in that effort," said J. Andrew McCammon, holder of the Joseph Mayer Chair of Theoretical Chemistry at UCSD and a Howard Hughes Medical Institute Investigator.
The study, published in the Journal of Medicinal Chemistry, builds on prior work that captured the nanosecond-by-nanosecond movements of a protein called neuraminidase 1 (or N1), needed by the avian flu virus to spread infection to new cells.
To help reveal the often-spasmodic motion of proteins, scientists work with molecular dynamics codes that simulate their movements as they obey the fundamental laws of physics.
In their latest work, the scientists conducted a "virtual screen" of an ensemble of 1,883 compounds selected from the National Cancer Institute Diversity Set, using a computational tool called AutoDock that predicts how small molecules, such as drug candidates, bind to a receptor of a known three-dimensional structure.
The goal was to try to determine which compounds fit best into the "hot pocket" region of N1. Generally, compounds that most easily bound to the site are considered to be top hits for validation and further optimization as drug candidates.
Five other compounds known to experimentally bind to avian influenza N1 were also screened, including drugs now available or in clinical trials.
The results were intriguing. About 27 compounds showed significant promise, all having potentially the same or stronger bonding affinity than current anti-flu drugs now available, including Tamiflu and Relenza.
Several looked like particularly good candidates, Amaro said, since they bound to both the regular active site and an additional side pocket that opened during the computer simulation.
"The general idea is that we will be able to make a better drug through the strategic targeting of multiple active site pockets," said Amaro.
The research now moves into the lab, where the compounds will undergo testing against the virus. Researchers at the Scripps Research Institute in La Jolla, California will lead this phase of the research.
(Xinhua News Agency July 3, 2008)