DURHAM, N.C. -- By developing software that uses 3-D models of proteins involved in cystic fibrosis, a team of scientists at Duke University has identified several new molecules that may ease the symptoms of the disease.
Computer algorithms created by the team predict how well a given molecular structure will block a basic protein-protein interaction known to occur in cystic fibrosis. To test the predictions, the scientists synthesized the molecules and measured how well they attached to one of the proteins in that interaction. The team then placed the best molecule into human cells with the cystic fibrosis mutation in a laboratory dish and found that their new drug blocked the protein-protein interaction and increased the cells' ability to balance salt and water levels.
The results, which appear in the April 19 Public Library of Science Computational Biology, suggest that computers could make drug design for cystic fibrosis faster.
"We have known the genetic cause of cystic fibrosis since 1985. Now, by understanding its biology and chemistry, we can design and create targeted drugs to correct for the genetic flaw," said Bruce Donald, a Duke computer scientist and biochemist who led the study.
Cystic fibrosis, or CF, is a childhood disease causing the lungs and pancreas to fill with mucus, making it hard to breathe and absorb nutrients from food. The mucus builds in the organs as the levels of salt and water in the cells become unbalanced because of a defective protein.
That protein, called CFTR, the cystic fibrosis transmembrane conductance regulator, regulates salt and water in the cell. In CF, it is defective because the genes that generate it are mutated. CFTRs are routinely rounded up for recycling in the cell by a protein called CAL that binds to CFTR and hauls it away. But defective CFTR proteins in cystic fibrosis patients send a signal that they are faulty, making their recycling rate much higher.
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