Chemists develop frameworks that enable efficient synthesis of “information-dense” molecules-ScienceDaily

Such molecules are common in plants and other organisms and are often considered the preferred starting point for developing potential new drugs. However, it also tends to be very difficult for chemists to build and modify in the lab. This is a process called synthesis.

Using a theoretical framework centered around computer modeling and the concept of “information density,” the team used the chemical principles underlying the 2019 breakthrough synthesis of bilobalide molecules produced in the leaves of Ginkgo biloba. I made it clear. Bilobalide is a particularly complex and compact molecule that has been shown to be promising as a potential neurological or psychiatric drug.

Scientists believe that the theoretical results of their new research, published in the Journal of the American Chemical Society, will allow chemists to devise more efficient synthesis of such challenging natural molecules. Masu-Pharmaceuticals and other products that have the potential to open up new areas of powerful bioactive compounds.

“When we first achieved the synthesis of bilobalide, we were essentially following intuition, but in this new study we understand how chemistry actually works and apply it to other challenges in organic synthesis. We have developed a principle that we think we can do. ” Dr. Ryan Schenbi, a professor of chemistry at Scripps Research and the lead author of the study.

Creation of precious natural compounds

Bilobalide, which evolves in ginkgo trees and has a high potential to protect its leaves from insects, blocks an insect neuronal receptor called RDL. The fact that this molecule kills insects, but is very safe in mammals and rapidly dissipates in the environment has attracted interest in safe crop protection.

Bilobalide is highly expected for medicinal use, with evidence that it is relatively safe for humans. It blocks a human brain cell receptor called the GABAA receptor, the evolutionary cousin of the insect RDL receptor. An interesting 2007 study found that this compound could reverse cognitive and memory deficits in mice with neurological states that modeled Down’s syndrome in humans, but other studies have shown that certain types It has been suggested that it may protect brain cells from the harmful effects of.

Natural bilobalide is synthesized by a special enzyme in the cells of Ginkgo biloba, but chemists want to be able to make it in the laboratory using organic chemistry techniques. In this way, they can obtain large amounts of compounds and modify them to investigate and optimize their properties.

However, the synthesis of bilobalide has always been a major challenge for scientists. This is because the molecule packs a relatively complex set of atoms containing eight reactive oxygens into a strange and very compact chemical structure. If they can overcome that challenge, chemists will have a way to create potentially enormously valuable molecules.

“When you have that degree of condensed complexity, you start to see interesting emergent traits,” says Schenbi.

“Information density” brings a deep understanding

In this study, Shenvi and his colleagues evaluated the 11-step synthesis of bilobalide achieved in 2019 and the two longer previously published bilobalide synthesis.

With the help of collaborators Kendall Houk, PhD, computational modeling by Saul Winstein Distinguished Research Chair of organic chemistry at UCLA, and the formal theory of “molecular information content” published in 2016 by German researcher Thomas Böttcher. They used “information density” (essentially complexity divided by molecular weight) to analyze bilobalide synthesis.

Their analysis shows that bilobalide has a very high information density compared to other naturally occurring compact and biologically active molecules, the amount of information mainly derived from its oxygen atom and asymmetric carbon skeleton. Showed to do.

The study reveals that the synthesis of bilobalide by the Shenvi lab is efficient due to fragment coupling (merging of already complex oxygen-containing molecules) and careful modifications to overcome the abnormal appearance properties of the system. became.

The team’s developed chemical principles understand higher efficiency than bilobalide synthesis and previous synthesis, but researchers say it can also be applied to many other open problems, including natural molecular synthesis. ..

As part of the work, co-authors Stefano Forli and PhD created computer scripts in the Python coding language to automate the calculation of molecular information at speeds of over 100,000 molecules per minute. (The script is available for download.) Forli is an assistant professor of integrated structure and computational biology at Scripps Research.

Collaborator Dr. Marisa Roberto, a professor of molecular medicine at Scripps Research, studied the activity of bilobalide and another information-dense molecule recently synthesized by Shenvi’s team. In rodent studies, she found that both bilobalide and diaziphenolide were promising as relatively potent and safe GABA A blockers, which could be converted to drugs for mental states with abnormal GABAA activity Suggests.

“The GABA system changes dramatically with neuropsychiatric disorders such as alcoholism and other forms of addiction. One or both of these compounds may one day help,” says Roberto.