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Inside the ‘Molecular Library’ With 4M Compounds Used to Investigate Potential Medicines

For scientists seeking to create new medicines, the building blocks of their therapeutic ingenuity are often found in the existing substances that their colleagues and predecessors have created through decades of painstaking research.

That’s one reason it’s awe-inspiring to behold the 4 million liquid compounds neatly stacked in carousels of what amounts to a molecular library, stored and curated at Pfizer’s facilities in Groton, Connecticut. This collection has been called the company’s “crown jewels” — continuously updated and accessed by scientists searching for new medicines. Some of the latest medicines developed can be traced back to this collection.

And a recent upgrade in how those compounds are stored and shipped out to scientists far and wide has put a state-of-the-art twist on the crucial task. Spearheading that upgrade was Rose Gonzales, Director of Compound Management and Distribution at Pfizer.

“It would take about 60,000 man-years and $5 billion to resynthesize the entire collection. So, essentially, it’s irreplaceable,” says Gonzales, a chemical engineer by training. In order to test a compound that has been used up or destroyed, it would be necessary to resynthesize the compound, so appropriate stewardship of the samples is important. 

“Part of our job is to make it last for as long as we can, but at the same time, make people more aware of it so they can capitalize on it and use it for their research,” she adds, referring to the fact that even though scientists within the company may be aware of the compound library, they may not realize the breadth and variety it contains, and how it can aid their research. 

Since 2004, four robots have been working perpetually in a chilled warehouse, converted from a former shopping center, selecting those compounds so that some 10 million samples of those compounds can be delivered to experiments conducted at all Pfizer sites and by research partners around the world. But with those robots reaching the end of their lifespan, the compound library was at risk of shutting down for three to six months for a major overhaul.

“That would’ve been a no-go. You can’t not have access to the collection for that long,” Gonzales says of the interruption it would have caused to ongoing research.

So, she led an effort to make the library fit in a new, smaller space without any downtime, while also making the liquids last longer and reducing plastic waste associated with the older dispensing methods.

The pivotal technology used in the new library is something called acoustic droplet ejection (ADE), which allows liquid compounds to be transferred from storage plates to destination plates using a pulse of sound energy. A plate has hundreds of “wells” — tiny divots that can hold a few droplets of liquid. Each sound pulse transfers 2.5 nanoliters of liquid, and the typical amount shipped to a scientist is 100 nanoliters.

“If I have 5 microliters to start with, and I only shoot 100 nanoliters at a given time, that’s 50 uses of that single compound,” Gonzales notes. “The technology has really enabled us to preserve the samples that we have.”

The new facility uses storage plates about the size of your hand that have 1,536 wells — four times as many as the older plates. That compactness allows the carousels to sit on a smaller footprint — what Gonzales affectionately calls the “studio apartments” as opposed to the “mansion” that was the older facility.

The modern plate has 1,536 wells, four times as many as the older plates.

As long as the humidity is controlled, the compounds can sit at room temperature, eliminating the need for refrigeration. And the new acoustic dispensing technology saves over $500,000 a year in single-use plastic consumables alone.

Another new technology used in research to find compounds of interest is called affinity selection mass spectrometry (ASMS) which allows for even more compact storage by storing about 100 compounds in the same well without the risk of cross-contamination. In this screening technology, the target compound is selected using a binding protein to pick it out from the chemical stew. It’s akin to using a keyhole to sort through a bunch of keys stored together randomly.

A robotic carousel holds hundres of plates. 

About 100,000 to 250,000 new compounds are added to the collection every year, Gonzales says, and it can get occasional infusions of tens of thousands of compounds when Pfizer acquires an outside collection.

There are also multiple backups of the compound library, including at the facility at the converted shopping center site, which uses an older plating technology. In fact, there are so many of those plastic plates that if you stacked them all up flat, they would be twice as tall as the Burj Khalifa, the tallest building in the world, Gonzales notes.

One function of the compound library is to work with scientists to make sure their requests are optimized — not only to preserve the compounds, but also to help the scientists conduct their experiments more efficiently. 

Rose Gonzales, Director of Compound Management and Distribution at Pfizer.

 

Last year, a collaborator requested compounds in amounts that would have consumed a significant amount of stock. Rather than automatically fulfilling the request, Gonzales spoke to the team to find out pertinent details of their assay. “We came back with a proposal that only consumed 1.2 microliters of stock for one set of compounds and 750 nanoliters for another set. These amounts allowed them to screen two different concentrations in triplicate.”  

The new system also saves a great deal of time for the scientists receiving the samples, because they don’t have to prepare the plates manually — which is an extremely time-consuming process, particularly for large numbers of compounds used for what’s known as high-throughput screening.

“A request for 20,000 or 50,000 compounds is not out of the norm,” Gonzales notes.

And the new technology is integral to what Gonzales calls “immortalizing the collection” of compounds — that is, making these crown jewels last for as long as they can while still using them.

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