"The treatment of receptor flexibility with molecular dynamics simulations played a critical role in understanding the mechanism of action for this new class of inhibitors," said McCammon, a professor of Pharmacology at UC San Diego.
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 bind 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.
Added Cheng, former Pacific Rim Experience for Undergraduate student and NBCR researcher: "Importantly, half of these compounds would have been neglected based on the crystal structure simulations alone. Many of t
|Contact: Warren R. Froelich|
University of California - San Diego