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Meet Vanderbilt’s molecular architects

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Group photo of The Molecular Design and Synthesis Center. From left, Gary Sulikowski, Kwangho Kim, Alex Waterson, Plamen Christov, Benjamin Guttentag, LaToya Scaggs, Ian Romaine, KyuOk Jeon, and Somnath Jana.
The Molecular Design and Synthesis Center is staffed by talented researchers. From left, Gary Sulikowski, Kwangho Kim, Alex Waterson, Plamen Christov, Benjamin Guttentag, LaToya Scaggs, Ian Romaine, KyuOk Jeon, and Somnath Jana. Photo by John Russell.

By Stephen Doster and Carol Rouzer

Vanderbilt’s Chemical Synthesis Core, recently renamed the Molecular Design and Synthesis Center, celebrated a decade of work this year. To commemorate the anniversary, we sat down with Gary Sulikowski, Stevenson Chair of Chemistry and faculty director of the center since 2008, who shared insights into synthetic chemistry and discussed the center’s history and involvement in drug discovery at Vanderbilt.

What is the purpose of the MDSC?
The main purpose of the core has always been to support the synthetic chemistry needs of Vanderbilt investigators across campus. As synthetic chemists, we can describe ourselves as molecular architects. We first design a molecular structure on paper, and then, using the tools of organic chemistry, we build the molecular structure in our lab and place it a bottle for study by the investigator’s lab.

We focus on two main goals. The first is to support preclinical lead optimization in drug discovery. This is the process where we make structural changes to an active hit compound—a molecule that looks like it has a biological activity of interest—to improve its physical and biological properties. The goal is to make the compound more drug-like so that it can be used in animal models.

Our second main goal is to help researchers who are not necessarily interested in drug discovery acquire or develop chemical tools that will help them better understand biological processes from a basic science perspective. For example, some projects require that we create synthetic processes to provide investigators with large amounts of natural metabolites or drug-like compounds in the quantities needed for animal studies.

What’s one of the center’s proudest successes?
One notable success was making a compound called bacillithiol, a member of the wider class of thiols, which are compounds that often play an important role in cells by destroying certain types of toxic metabolites.

Chemical structures of bacillithiol and bacil-lithiol disulfide.
Chemical structures of bacillithiol and bacillithiol disulfide.

At the time of bacillithiol’s discovery, the late Professor of Biochemistry Richard Armstrong was interested in the role of thiol compounds in the ability of bacteria to develop resistance to the antibiotic fosfomycin. He thought the bacteria that make bacillithiol might have been using it for this purpose. He could not test this hypothesis, however, because bacillithiol was only available in minute quantities. There was no known lab-based synthesis of the compound then, but we developed a method to do it in large quantities.

To this date, I think we’re one of only two groups that have ever prepared this compound, and it’s not uncommon for us to get requests from investigators outside of Vanderbilt—from Switzerland and Israel, for instance—for bacillithiol to support their studies of pathogenesis or other functions in bacteria.

Has COVID-19 affected perceptions about chemical synthesis and drug discovery?
Oh, yeah. One silver lining about the pandemic is that it has highlighted the importance of drug discovery and is advancing our understanding of infectious diseases. Early on during the pandemic, Professor Steve Fesik had an idea for a possible drug to target SARS-CoV-2, the virus that causes COVID-19. To test his hypothesis, he needed material quickly, and we were able to ramp up and give him some initial synthetic support, providing early lead molecules designed by his team.

This example illustrates why we’re also sometimes referred to as a SWAT team. We
are known for our ability to mobilize and help support researchers quickly. Typically, our
seven talented investigators work on over 20 ongoing projects in the core at any one time.

 

For more information about the center and its successes, read “Ten-Year Retrospective of the Vanderbilt Institute of Chemical Biology Chemical Synthesis Core,” published in ACS Chemical Biology on May 21, 2021, or visit the center’s website: vanderbi.lt/syncore

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