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iSGTW Feature - Preventing human-transmissible avian flu

Feature - Grid helps to clip the wings on avian flu

The simulated tetramer neuraminidase (N1) system is shown encased in a water bath. (Pink, purple, red and green objects are all N1; represented in "skeleton" and "skin" images, respectively. The colors are not significant.) One chain is shown with a green molecular surface (skin) representation. Oseltamivir (also known as Tamiflu, the only effective drug available orally) is shown bound in yellow within each of the active sites of the (green) N1 enzyme. Oseltamivir is represented as blue, red and white ball-and-sticks in the other portions.

Image courtesy of NBCR.

To date the avian flu virus is not transmissible among humans, however it mutates constantly and some strains have already become resistant to current anti-viral drugs. With the possibility of a worldwide outbreak ever-present, the search for new, more powerful drugs is vital.

Using resources at the San Diego Supercomputing Center (SDSC), a team of University of California San Diego scientists has identified more than two dozen compounds that are promising candidates for use in new avian flu drugs. These compounds may prove to be equal or stronger inhibitors than what is currently available, says UC San Diego chemistry postdoctoral fellow Rommie Amaro.

The avian flu virus, sheathed in a protein cover, infects cells in its host and then uses a protein called neuraminidase 1 (N1) to detach itself from the host cell and spread to other cells. To fight the virus, scientists use inhibitor drugs that attach like puzzle pieces to binding points, called active sites, on N1 and prevent it from detaching the virus from the host cell.

A close-up view of one of the computationally-derived neuraminidase (N1) active sites is shown, with several compounds docked into the binding pockets, indicating that these newly discovered pockets may favorably bind new anti-viral compounds. Oseltamivir is is drawn in black for reference.

Image courtesy of Rommie Amaro.

Designing drugs around movement

In order to identify potential new inhibitor drugs, scientists must find compounds that fit into N1's active sites. But proteins are not static organisms; they are dynamic molecular machines, and the active sites are flexible and move with the protein. Scientists must take this motion into account when looking for target sites for compounds.

To predict how N1 moves and to identify new target sites on it, the UC San Diego team ran a series of massively parallel, physics-based molecular dynamics simulations on SDSC's DataStar system using NAMD2. The dynamic protein simulations are vital to discovering new compounds because they show the protein's movement. This cannot be seen in static crystallography images.

"The new protocol in computer-aided drug design is trying to take into account the movement of these molecular machines and how to design drugs around those movements," Amaro says.

Her team's simulations indicated new, previously unobserved pockets within an active site in N1. Using a computational tool called AutoDock on the simulation results, the team ran processor compute jobs to screen 1,833 compounds using the Pacific Rim Application and Grid Middleware Assembly (PRAGMA) grid and the National Biomedical Computation Resource (NBCR) cluster. From the results, they found 27 compounds showing promise of fitting into the newly identified N1 target sites.

Promising though they are, the compounds must be experimentally tested against the virus. "Right now these are just computational predictions," Amaro says. "The real excitement will come when some of these compounds are validated to be new real inhibitors in the lab."

-Amelia Williamson, iSGTW

This work involved the support of several projects, including CTBP, PRAGMA and the Pacific Rim Experiences for Undergraduates (PRIME) supported by NSF; the National Institutes of Health National Biomedical Computation Resource (NBCR) supported by NCRR, NIH; and Avian Flu Grid, supported by and TATRC and participating PRAGMA member institutions.

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