Purdue researcher invents molecule that ...(urnal Proceedings of the National Acade...)

Mesecar's team screened more than 50,000 chemical compounds for the necessary properties to both block the virus and have the potential to become viable drug treatments.

"Only two of the compounds we tested were identified as having the properties researchers believed could become drugs," said Mesecar, a professor of medicinal chemistry and pharmacognosy. "Using those two compounds, Arun Ghosh and his team increased the potency by almost two orders of magnitude."

Ghosh, who invented the HIV drug darunavir that entered the market in 2007, specializes in improving the treatment properties of molecular inhibitors through structure-based design.

"The design of this inhibitor was a challenge because we did not know the structure of the compound, which shows us how an inhibitor works and what parts need to be amplified or changed," Ghosh said.

Kiira Ratia, a graduate student at the University of Illinois, provided a breakthrough when she captured the X-ray structure of the inhibitor molecule bound to the protein. The structure confirmed that the inhibitor would be a good candidate for drug development because it showed that the inhibitor did not bond too strongly to the protein, Ghosh said.

"This was the first time the structure was revealed and we could see that the inhibitor filled the active site of the protein without using strong covalent bonds," he said. "This is very important for development of a therapeutic treatment because it means there is less of a chance for adverse side effects or toxicity, and the treatment can be easily reversed."

Often a protein involved in the disease process also plays a role in regular human biological processes. A safe and effective treatment needs to block enough of the protein to cripple the disease while not completely eliminating the protein from a person's system. It also must work through interactions tha
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