Werner Kaminsky, a crystallographer and UW professor of chemistry, closely studied a molecule called humulones, which is found in bitter beers, and his results contradicted previous findings about the molecule. His findings were published in the scientific journal Angewandte Chemie last week.
Kaminsky’s studies involved identifying the structure of the humulones molecule by using technology called X-ray crystallography. The atoms diffract the X-ray beams in a way that shows the molecule’s structure. Yet through his research, he discovered something else. Previous research hadn’t found handedness and assumed uniformity between the molecules.
Handedness results when a molecule can be arranged in two different ways with the same atoms. Jan Urban, a chemist who worked on the project with Kaminsky, said the handedness of a molecule is like the difference between a left hand and a right hand — they are the same but differently arranged. He said handedness can have huge effects on how the molecule works in pharmaceuticals.
“To me, it was surprising that something was out there for 40 years, and it’s wrong,” he said. “Nobody seemed to come across that so far.”
Kaminsky’s research was conducted for a Seattle-based pharmaceutical company called KinDex Therapeutics, which is working to use this molecule in a therapeutic drug to treat people with glucose management issues and insulin sensitivity. The company is now performing more trials of this molecule for use in treatment.
“We wanted to really get it right,” Kaminsky said. “It’s not being secretly done, and it’s not to prove someone wrong. It’s just to get the right result.”
Urban said the beer compound has a variety of benefits, but correctly identifying the structure was the project’s primary focus.
“Imagine if you go to play baseball, and you are going to buy a baseball mitt, you should be pretty certain whether you are buying it for right-handed or left-handed player,” he said. “If you don’t get the structure right, it will be really difficult to find where the compound binds.”
An example of handedness’ significance appeared in the drug Thalidomide in the 1950s, which was produced and distributed to pregnant women to decrease nausea and for use as a sleeping pill. Because scientists at the time didn’t know the handedness of the molecule, one orientation caused birth defects while the other orientation did what the pill was designed to do.
“The discovery of the handedness, or the absolute stereochemistry, has profound implications for the use,” said Brian Carroll, director of chemistry at KinDex. “So when you know the absolute stereochemistry, you can use that information to design new and improved compounds that may be even better in terms of their therapeutic effects.”
Kaminsky’s choice to use X-ray crystallography, a 100-year-old technology was simple.
“Being such an old technology, people say that there must be something better or something new,” Kaminsky said. “But that’s not very true. It’s not a bad technology; it’s very good. It’s the oldest nanotechnology, because we actually see objects on the size of several nanometers, which is the size of molecules, down to less than that so one nanometer is typically the size of a molecule.”
Carroll and Urban think that crystallography is the best way to determine a molecule’s structure.
“There are many ways to figure out the structure of a small molecule,” Carroll said. “Sometimes we as chemists don’t think of X-ray crystallography as the very first tool to use.”