A picture is worth 1,000 words when it comes to understanding how things work, but 3D moving pictures are even better. That's especially true for scientists trying to stop cancer by better understanding the proteins that make some chemotherapies unsuccessful.
Researchers for decades have had to rely at best on static images of the key proteins related to recurring cancers.
Now SMU biochemist John G. Wise at Southern Methodist University, Dallas, has brought to life in a moving 3D computer model the structure of human P-glycoprotein, which is thought to contribute to the failure of chemotherapy in many recurring cancers.
"This is a very different approach than has been used historically in the field of protein structure biochemistry," Wise said. "Historically, proteins are very often viewed as static images, even though we know that in reality these proteins move and are dynamic."
The model is a powerful new discovery tool, says Wise, particularly when combined with high-performance supercomputing. The dynamic 3D model already has made it possible for Wise to virtually screen more than 8 million potential drug compounds in the quest to find one that will help stop chemotherapy failure. http://bit.ly/MeUFOo
So far, the supercomputer search has turned up a few hundred drugs that show promise, and Wise and SMU biochemist Pia Vogel have begun testing some of those compounds in their wet lab at SMU.
"This has been a good proof-of-principle," said Wise, a research associate professor in the SMU Department of Biological Sciences. "We've seen that running the compounds through the computational model is an effective way to rapidly and economically screen massive numbers of compounds to find a small number that can then be tested in the wet lab."
Wise describes his research findings in Biochemistry in the article "Catalytic Transitions in the Human MDR1 P-Glycoprotein Drug Binding Sites" online at http://bit.ly/LBagWA.
The research is funded by the National Institute of General Medical Sciences, National Institutes of Health.
Seeking new drugs that would allow chemotherapeutic compounds to enter and destroy cancer cells
Since the 1970s it has been known that the so-called multidrug resistance protein, P-gp, is most likely responsible for the failure of many chemotherapy drugs. P-gp is nature's way of pumping toxins from a cell, but if cancer cells express more P-gp than cells normally would, the chemotherapy is no longer effective because the protein considers it a toxin and pumps it out before it can destroy the cancer.
"We're looking for small molecules that will temporarily inhibit the pump; a new drug that could be co-administered with the chemotherapeutic and that stops the sump pump in the cancer cell so that the cancer chemotherapy can remain in the cell and kill the cancer," Wise said.
High-performance computer enables millions of digital screenings
Wise has run about 10.5 million computational hours since August 2009 and has screened roughly 8 million potential drugs against different protein structures.
"We are currently screening about 40,000 compounds per day on SMU's High Performance Computer," Wise said.
"We found a couple hundred compounds that were interesting, and so far we chose about 30 of those to screen in the lab," Vogel said. "From those, we found a handful of compounds that do inhibit the protein. We were thrilled. Now we're going back into the models and looking for other compounds that might be able to throw a stick in the pump's mechanism."
Massive increases in computational power in recent years have made the screening research possible, Wise said. "Ten years ago you couldn't have docked 8 million compounds - there just wasn't enough computational power."
Human P-gp: "We don't know what it looks like exactly."