In a new study where a scientist drops the jaw, the joint UCLA / Caltech research team has shown that within 30 minutes a small molecule structure such as certain hormones and drugs can be obtained. It takes much less time.
The team used a technique called micro-electron diffraction (MicroED), which has been used in the past to learn the structure of large molecules, especially proteins. In this new study, researchers show that this technology can be applied to small molecules and that the process requires much less preparation time than expected. Unlike related technologies – some involve the growth of salt particle size crystals – as shown in the new study, this method can be used with ordinary starting samples, sometimes scraped from the beaker side.
"We took the lightest specimen you can get and almost always got top quality structures," said Caltech professor of chemistry Brian Stoltz, co-author of the new study, ACS Central Science. "When I first saw it, my chin hit the floor." This article, which was first released in Chemrxiv pre-print servers in mid-October, has seen more than 35,000 times.
This method works well in small molecule samples because the sample may appear to be a simple powder but actually contains a small crystal that is about a billion times smaller than a small dust. The researchers knew about previously hidden microcrystals, but did not know that they could easily identify the molecular structure of the crystals using MicroED. "People do not know how common these particles are in powder samples," Stoltz says. "It's like a science fiction.I did not think it would happen in my entire life.I could have seen the structure with powder."
The result suggests to chemists who want to determine the structure of small molecules, defined as small molecules of about 900 daltons or less. These mutations include certain chemicals found in nature, some biological substances such as hormones, and various treatments. Possible applications of the MicroED structure discovery methodology include drug discovery, crime lab analysis, and medical testing. For example, according to Stoltz, this method can be useful for testing the latest performance enhancing drugs for athletes with very little chemical presence.
"The slowest step in creating a new molecule is to determine the structure of the product, which may not be the case anymore because it promises to revolutionize organic chemistry," says Robert Grubbs, Professor of Caltech's Victor and Elizabeth Atkins . The 2005 Nobel Prize in Chemistry, which did not participate in this study. "The last major break for previous structural determinations was nuclear magnetic resonance spectroscopy, which was introduced by Jack Roberts at Caltech in the late '60s.
Like other synthetic chemists, Stoltz and his team are trying to figure out how to assemble chemicals as a starting material in the lab. Their lab focuses on natural small molecules such as fungus-derived beta-lactam compounds associated with penicillin. In order to make this chemical, both the neutral molecule and the end product must be checked for correct molecular structure in the reaction.
One technique to do this is X-ray crystallography, which involves the X-ray diffracting atoms into a chemical sample. The diffracted X-ray pattern represents the 3-D structure of the target chemical. Often this method is used to solve large molecule structures such as complex membrane proteins, but it can also be applied to small molecules. The problem is that in order to perform this method, the chemist must make large chunks of crystals in the sample, which is not always easy. "I spent several months trying to get the right decision for one of my samples," Stoltz says.
Another reliable method is NMR (nuclear magnetic resonance). This method does not require crystals but requires a relatively large amount of sample. NMR also provides indirect structural information only.
Previously, MicroED, which is similar to X-ray crystallography but uses electrons instead of X-rays, was mainly used for crystallized proteins and not for small molecules. Tamir Gonen, UCLA's electronic determinator, began developing MicroED technology for proteins at the Howard Hughes Medical Institute in Virginia, who said he started thinking about using the small molecule method after moving to UCLA. Caltech and.
"Tamir was using this technology in proteins and sometimes could only work with protein powder samples," said Dr. Hosea Nelson, PhD's assistant professor of chemistry and biochemistry at UCLA. The mind flew out of this and did not have to raise the crystal. By the time the team started to realize that this method could be applied to a completely new class of molecules that affect all types of chemistry extensively. "
The researchers tested several samples with different properties without crystallization, and the rich microcrystals of the sample allowed the structure to be determined. They have succeeded in obtaining structures for the base samples of the brand-name drugs Tylenol and Advil, and a clear structure has been identified from a mixture of powders of four chemicals.
The UCLA / Caltech team says it hopes this method will be routinely done in future chemistry labs.
"In our laboratory there are students and postdoctoral researchers who make new and unique molecular entities every day." Now we will change the synthetic chemistry because we have the power to quickly identify what they are, "says Stoltz.