In the field of chemistry, structure dominates everything because it determines how a molecule behaves. But there are two short-form methods for mapping two small organic structures, such as drugs, hormones, and vitamins. Recently, two research teams reported that they used a third technique commonly used to map larger proteins to determine the exact shape of small organic molecules. This new technology is effective for small, undetectable samples, and is extremely fast and simple.
"I was completely shocked by this technology," said Carolyn Bertozzi, a chemist at Stanford University in the United States. "The fact that you can get these structures from a sample that is only one millionth of a grain of dust is wonderful. For the chemical field, this marks a new day."
The gold standard for determining chemical structure has been X-ray crystallography. A beam of X-rays is emitted to a pure crystal containing millions of copies of one molecule. These molecules are arranged in one direction. By tracking how X-rays bounce off atoms in the crystal, the researchers can clarify the position of each atom in the molecule. Crystallography can precisely position atoms to less than 0.1 nanometers – about the size of sulfur atoms.
However, this technique works best in relatively large crystals that are difficult to manufacture. Caltech organic chemist Brian Stoltz said, "The real delay is getting crystals. This can take weeks, months, or even years." Known as the second nuclear magnetic resonance (NMR) spectroscopy, this method does not require a crystal. It infers the structure by disturbing the magnetic behavior of atoms within the molecule and tracking its behavior. The change in atomic magnetic behavior depends on its neighbors. However, NMR also requires a significant amount of raw material. At the same time, it is indirect, and for larger molecules like drugs, it can lead to drawing errors.
The latest method is based on a technique called electron diffraction. As with X-ray crystallography , this technique emits an electron beam and passes it through a crystal, and then determines the structure based on the diffraction pattern. This applies in particular to the structure of a class of proteins that remain in the cell membrane. In this case, the researchers first formed tiny two-dimensional plate crystals. These crystals consist of multiple copies of the protein "into the cell".
But in many cases, efforts to grow protein crystals can go awry. What the researchers finally got was a myriad of crystals stacked together instead of a single crystal. They cannot be analyzed by conventional electron diffraction. At the same time, these crystals may be too small to perform X-ray diffraction.
"We don't know how to handle these crystals," said Tamir Gonen, an expert in electronic crystallography at the University of California, Los Angeles (UCLA).
To this end, his team made a change to the technology: they rotated the crystal and tracked how the diffraction image changed, rather than emitting electrons from one direction toward the static crystal. They get results that are more like molecular computed tomography than a single image. This allows it to analyze crystal structures that are only one-billionth of the crystals required for X-ray crystallography.
Gonen said that because his interest lies in protein, he never thought about trying this technique on other things. But earlier this year, Gonen moved to the UCLA from the Howard Hughes Medical Institute's Jennifer Research Park. There, he and his colleagues and Stoltz from Caltech formed a team. Stoltz wants to know if the same method works not only for proteins but also for smaller molecules.
The short answer is “yes”. On the chemical preprinter server ChemRxiv, the team recently reported that when they applied this method to a variety of samples, they worked almost every time, and the resolution achieved was comparable to X-ray crystallography. They can even get the structure of the compound mixture. The structure of a substance that has never been officially crystallized and has just been scraped off from a chemical purification column can also be observed. These results can be released shortly after a few minutes of sample preparation and data collection. More importantly, a team of German and Swiss scientists used similar techniques to publish similar results.
Tim Grüne, an electron diffraction expert at the Paul Scherrer Institute in Switzerland, said that pharmaceutical companies have built huge libraries of crystalline compounds for potential new drugs. However, only about 1/4 to 1/3 of the compounds form crystals large enough to perform X-ray crystallographic analysis. "The latest research will eliminate this bottleneck and bring about a major outbreak of structural research," Grüne said.
This speeds up the search for potential drug leads in tiny samples of exotic plants and fungi. For forensic laboratories, the latest research will help them quickly identify the latest heroin derivatives that appear on the streets. It can even help Olympic officials find even more traces of stimulants. All of this is because the structure dominates everything, and deciphering the structure is now easier.
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