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Supercomputers fight against bird flu

A worldwide outbreak of avian or 'bird flu' is still not excluded and health officials recognize that new drugs are needed since new strains of the virus appear everyday. Now, U.S. scientists are using supercomputers to find new drugs to fight the virus and to stay ahead of these mutations. And it is encouraging to learn that a team of UC San Diego scientists has isolated more than two dozen promising and novel compounds from which new 'designer drugs' might be developed to combat this disease. The 27 new identified compounds appeared to be equal or stronger inhibitors than currently available anti-flu drugs like Tamiflu. But read more...
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Written by Roland Piquepaille, Inactive on

A worldwide outbreak of avian or 'bird flu' is still not excluded and health officials recognize that new drugs are needed since new strains of the virus appear everyday. Now, U.S. scientists are using supercomputers to find new drugs to fight the virus and to stay ahead of these mutations. And it is encouraging to learn that a team of UC San Diego scientists has isolated more than two dozen promising and novel compounds from which new 'designer drugs' might be developed to combat this disease. The 27 new identified compounds appeared to be equal or stronger inhibitors than currently available anti-flu drugs like Tamiflu. But read more...

Identifying potential drugs against bird flu

You can see above several pictures showing how the researchers worked. "Using protein structures generated by supercomputers, these renderings of the neuraminidase enzyme may help scientists identify potential new drug candidates to fight Avian flu, as strains of the disease become ever more resistant. Potential candidate drugs are shown docked into the neuraminidase active site in panels A-D. Panel A shows the crystal structure protein; panels B-D show proteins generated with molecular dynamics simulations. The images were generated with the Adaptive Poisson Boltzmann Solver (APBS) and Python Molecular Viewer (PMV)." (Credit: Rommie E. Amaro, Lily S. Cheng, UC San Diego; source: San Diego Supercomputer Center, UC San Diego.) Here is a link to a larger version of the above illustration.

Here is a quote from Rommie Amaro, a UC San Diego chemist and member of the research team, about this project. "If those resistant strains begin to propagate, that's when we're going to be in trouble, because we don't have any anti-virals active against them. So, we should have something as a backup, and that's exactly why we're working on this."

The research team used supercomputers at the San Diego Supercomputing Center and the National Center for Supercomputing Applications in Urbana-Champaign, Illinois, to run "complex programs to mimic the movements of a particularly wiggly protein called neuraminidase 1 (or N1), which the avian flu virus uses to spread infection to new cells. As the proteins changed shape according to physical laws, the computers picked up a "hot pocket" that appeared to be quite dynamic and flexible and therefore a target for medicines aimed at stopping the infection process."

It's interesting to note that the team chose to use AutoDock, a free suite of automated docking tools available under the GNU General Public License and developed at the Scripps Research Institute. AutoDock "is designed to predict how small molecules, such as substrates or drug candidates, bind to a receptor of known 3D structure." The researchers used Autodock to test 1,883 compounds selected from the National Cancer Institute Diversity Set and found that "27 compounds showed significant promise, all having potentially the same or stronger bonding affinity with N1 than currently available anti-flu drugs."

A previous San Diego Supercomputer Center news release, "UC San Diego Researchers Identify Potential New Drug Candidates to Combat 'Bird Flu' (July 2, 2008), provides additional details on this research project.

For example, "some surprising details emerged as the scientists watched the protein gyrate and wiggle over time. In particular, one region -- dubbed a 'hot pocket' -- appeared to be quite dynamic and flexible. Amaro said the topology of this region and the amino acids linking the pocket are significantly different from what the scientists previously observed in a static image of the protein's crystal structure. 'Crystal structures are very important,' she said. 'They give us a real picture of the protein. But it's just one picture.'"

Lily Cheng, a former Pacific Rim Experience for Undergraduate student (PRIME) who is now a National Biomedical Computation Resource 'NBCR) researcher added: "Importantly, half of these compounds would have been neglected based on the crystal structure simulations alone. Many of these drug leads would only have been found through the use of this computational method." Here is a link to a a short video of Cheng describing her work. (2 minutes and 50 seconds)

This research work has been published in the Journal of Medicinal Chemistry under the name "Ensemble-Based Virtual Screening Reveals Potential Novel Antiviral Compounds for Avian Influenza Neuraminidase" (Vol. 51, Issue 13, Pages 3878–3894, July 10, 2008, but available online since June 18, 2008).

Here is the beginning of the abstract. "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)."

The full paper is available online, both in an HTML version and as a PDF document (17 pages, 3.13 MB).

Here are some excerpts from the conclusions. "Through eight different virtual screens of the NCI diversity set, which employed structures taken from crystallographic studies as well as representative structures from apo and holo MD [molecular dynamics] simulations, 27 drug-like ligands have been identified, which are predicted to bind with high affinity to avian influenza N1. Fourteen of these compounds are unique hits that would not have been found based on the crystal structure screens alone, and they include compounds that bind to flexible loop regions unseen in the crystal structures. [...] This novel strategy for identifying NA [neuraminidase] inhibitors may facilitate the design of better drugs in the fight against global pandemic influenza and be applicable in structure-based drug discovery initiatives."

Sources: Leslie Fink, National Science Foundation, for US News and World Report, July 14, 2008; and various websites

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