In a new study as a scientist called jaw case, a joint UCLA / Caltech team has shown that it…
In a new study as a scientist called jaw case, a joint UCLA / Caltech team has shown that it is possible to get the structures of small molecules, such as some hormones and drugs, in as little as 30 minutes. It’s hours and days less than was possible before.
The team used a technique called microelectric diffraction (MicroED), previously used to learn the 3-D structures of larger molecules, especially proteins. In this new study, researchers show that technology can be applied to small molecules, and that the process requires much less processing time than expected. Unlike related techniques – some of which means that the crystals are larger than the size of the brine – this method, as the new study shows, can work with startup samples, and sometimes even powders are sprinkled from the side of a beaker.
“We took the lowest eye samples you can get and get the highest quality constructions barely sometime,” said Caltech Professor of Chemistry Brian Stoltz, co-author of the new study, published in Journal ACS Central Science . “When I first saw the results, my jaw hit the floor.” Originally released on the Chemrxiv pre-print server in mid-October, the article has been shown more than 35,000 times.
The reason that the method works well on small molecule samples is that while the samples can act as simple powders, they actually contain small crystals, each about one billion times less than a vacuum cleaner. Researchers knew about these hidden microcrystals earlier, but did not realize that they could easily reveal the molecular structures of the crystals using MicroED. “I do not think people realized how common these microcrystals are in the powdery samples,” says Stoltz. “This is like science fiction. I did not think it would happen during my lifetime ̵
1; that you could see structures from powder.”
The results have consequences for chemists wishing to determine the structures of small molecules defined as those weighing less than about 900 daltons. (A dalton is about the weight of hydrogen.) These small compounds include certain chemicals found in nature, some biological substances such as hormones and a number of therapeutic drugs. Possible applications of the MicroED structure search method include drug detection, analysis of crime lab, medical testing and more. Stoltz says, for example, that the method can be used to test the latest performance enhancing drugs of athletes, where only trace elements of a chemical may be present.
“The slowest step in creating new molecules is to determine the structure of the product. It can no longer be the case because this technology promises to revolutionize organic chemistry,” says Robert Grubbs, Caltech Victor and Elizabeth Atkins Professor of Chemistry and a winner of the Nobel Prize for Chemistry in 2005, which was not involved in research. “The last major break in structural determination before was nuclear magnetic resonance spectroscopy, introduced by Jack Roberts at Caltech in the late 60’s.”
Like other synthetic chemists spending Stoltz and his team make their time calculating how to assemble chemicals in the lab from basic starting materials. Their laboratory focuses on such natural small molecules as the fungal-derived beta-lactam family of compounds related to penicillins. In order to build these chemicals, They determine the structures of molecules in their reactions – both the intermediates and end products na – to see if they are on track.
A technique for doing that is X-ray crystallography, where a chemical sample is encountered with X-rays diffusing from its atoms; The pattern of these diffractive x-rays reveals the 3-D structure of the targeted chemical. Often this method is used to solve the structures of really large molecules, such as complex membrane proteins, but it can also be applied to small molecules. The challenge is that in order to perform this method, a chemist must create good pieces of crystal from a sample, which is not always easy. “I spent months trying to get the right crystals for one of my samples,” says Stoltz.
Another reliable method is NMR (nuclear magnetic resonance), which does not require crystals but requires a relatively large amount of a sample, which can be difficult to collect. In addition, NMR only provides indirect structural information.
For now, MicroED – similar to X-ray crystallography but using electrons instead of X-rays – was used mainly on crystallized proteins and not on small molecules. Co-author Tamir Gonen, an electron crystallographic expert at UCLA, who started developing the MicroED technology for proteins at the Howard Hughes Medical Institute in Virginia, said he only began to think about using the method of small molecules after moving to UCLA and collaborating with Caltech.
“Tamir had used this technique on proteins and only meant that they could sometimes only work with protein proteins,” said Hosea Nelson (PhD, 13), Assistant Professor of Chemistry and Biochemistry at UCLA. “I was impressed that you did not have to grow crystals, and it was about the time the team started to realize that we could apply this method to a whole new class of molecules with far-reaching consequences for all types of chemistry.”
The team tested several samples of different grades, without ever attempting to crystallize them and could determine their structures thanks to the rich microcrystals of the sample. They managed to get structures for basic samples of brand names drugs Tylenol and Advil, and they could identify distinct structures from a powdered mixture of four chemicals.
The UCLA / Caltech team says it hopes that this method will be routine in chemistry laboratories in the future.
“In our laboratories, we have students and postdocs make brand new and unique molecular devices every day,” says Stoltz. “Now we have the power to quickly figure out what they are. This will change synthetic chemistry.”