Friday, August 3, 2012

Chemotherapy pump drives 3D drug design

Cancer treatment often fails because of p-glycoprotein, which pumps chemotherapies out of cancer cells before the drugs can kill them. Nearby healthy cells use the same protein to pump out thousands of toxins, so you can’t just shut it down with a drug.

What we need are chemotherapies that can evade the pump or drugs that clog it up only in cancer cells to keep chemo in them longer. But how can you begin to tell which molecules might be capable of such feats?

Crystallography and X-ray diffraction reveal the 3-D structural maps of disease-related proteins as a starting point for drug design. Researchers gain insight into an envisioned drug’s ideal shape from the map of its protein target, like making a key from the lock it must fit into.

Stephen Aller, Ph.D., assistant professor in the Department of Pharmacology and Toxicology within the UAB School of Medicine, first solved the crystal structure of p-glycoprotein in 2009, earning him a cover story in the journal Science and national recognition. Aller sat down with The Mix to share his amazing computer animation of the protein’s structure and take us on a photo tour of his lab.

Chemo pump drives 3D drug design from uabnews on Vimeo.

Show notes

0:33 Multi-drug resistance is driven by several mechanisms, but treatment efflux via drug pumps is a major contributor to treatment failure.

1:12 Molecular map-making is possible because proteins happen to form orderly, repeating stacks called crystals when you coax them close together in a solution.

1:38 X-ray diffraction involves bouncing X-rays off of the growing crystal, and then rebuilding the reflections into a map of the protein’s structure using with computer algorithms.

2:10 Virtual drugs based on the maps can be tested in computer simulations before you incur the great cost of making the would-be drug in the real world.

2:45 Protection provided by p-glycoprotein in healthy cells goes awry in cancer cells, which make more of it to pump out chemotherapies.

3:18 Screening efforts are under way to find chemotherapies that can evade the drug pump in cancer cells.

3:48 Molecular structure, revealed by crystallography, has enabled Aller’s team to fine-tune drug candidates that could one day block the pump in cancer cells.

5:26 Aller shares his favorite resources for those interested in crystallography, including the RCSB Protein Data Bank, where most of world's protein structures are stored, and PIMOL, a player for making animations like his. 

About the blogger

Greg Williams @gregscience @themixuab is research editor within Media Relations at the University of Alabama at Birmingham.

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