John Otrompke, JD
Medicinal chemistry makes a comeback
For more than a decade, combinatorial chemistry dominated drug discovery strategies. The idea of generating millions of compounds at a time almost guaranteed boatloads of blockbuster drugs. But it didn’t work out that way, and now it seems scientists are looking anew at some old approaches.
“Combinatorial chemistry started in the ’80s, and the whole idea was that ‘Wow, you could test millions of molecules and succeed,’ that was pretty revolutionary,” says Umesh Desai, PhD, associate professor of medicinal chemistry at Virginia Commonwealth University School of Pharmacy, Richmond, Va. “The pharmaceutical industry said that we should be able to come up with a molecule once every two months, but that never really materialized. The process was relatively slow; we were able to generate a few molecules per year,” he says. “The word on the street is that people are resorting back to traditional organic medicinal chemistry, and beefing up their medicinal chemistry programs,” adds Desai.
Quantity, not quality
In combinatorial chemistry, chemical moieties are added randomly to molecules that are affixed to a solid substrate. The method has been around for decades, long before automation popularized it in the 1990s. “Those technologies didn’t really mature, and nowadays industry has abandoned this concept,” says Klaus Mueller, PhD, head of science and technology relations at F. Hoffmann-La Roche.
Indeed, not only did the expected surge in productivity never materialize, but the number of new active substances hit a 20-year low of 37 in 2001, and is still declining.
One problem was that, while combinatorial chemistry generated huge databases of molecules, the process ultimately produced too few active molecules. “It was hard to say how much of any given ingredient was in there, and how they interacted with each other in the presence of the target. That’s because the impurity levels were much higher in those samples, with each compound ranging from 45% to 85% purity,” recalls Farah Mavandadi, PhD, product manager for Biotage, Uppsala, Sweden.
Expenses were also a factor in the method’s demise, says Mueller. “When you have an immense library to screen for efficacy, it costs millions of dollars to do a full screen of a million compounds.” Furthermore, “if you have just a 1.1% hit rate, you can easily run into problems. The molecules might be insoluble or too lipophilic, which can be problematic if we need a certain membrane permeation,” he adds.
To be fair, the combinatorial approach has produced its share of blockbusters with important ramifications for human health. Success stories include valium, librium, and other benzodiazepines that made a contribution to psychiatry in the middle of the last century. Still, that level of output is disappointing to drug-makers.
As a result, says Mavandadi: “A lot of departments are evolving into high-throughput medicinal chemistry groups. They still make compounds in large numbers, but the numbers are not as large as they used to be in combichem. There are groups who still make thousands, but on the average, groups make between 20 and 100 compounds every synthetic turn.Big pharmaceutical companies still tend to have departments that will make thousands of compounds, but they are much higher in purity today than they used to be,” she says. Mavandadi regularly talks with chemists at pharmaceutical companies about workflow issues. “And a lot of these libraries today are designed for a specific purpose, with a lot more thought behind their making,” she says.
“Biotech companies, on the other hand, tend to be more focused in their approach. They start off having a target or active ingredient in mind, so their focus tends to be on making smaller focused libraries,” says Mavandadi. She expects these newer techniques will result in drugs that will be in the field in several years.
A little of this, a little of that
Combinatorial chemistry has not fallen completely by the wayside, though. Instead, it serves as a general method for getting into the ballpark when developing therapeutic compounds; once “on the green,” scientists turn to medicinal chemistry, or other techniques, to develop more efficacious drugs, says David Pleynet, PhD, senior scientist at TorreyPines Therapeutics Inc., La Jolla, Calif.. The use of combinatorial chemistry followed by medicinal chemistry is known as parallel synthesis.
“The equipment for combichem might be on the expensive side, but you can make so many compounds, that it is a very cost-efficient way of discovering leads. The equipment allows you to set up 384 reactions at a time, and, in the long run, it is a very cost-efficient method,” he says. He notes that his lab uses a parallel synthesis technique that involves combinatorial chemistry to develop therapies for central nervous system diseases like Alzheimer’s.
Parallel synthesis was also a focus at Biotage, which provides tools for drug discovery. In recent years, the company made a number of acquisitions to allow high-throughput medicinal chemists to do parallel synthesis. One of these acquisitions is Argonaut.
“Argonaut made synthetic products that allowed for parallel synthesis but also resins,” says Mavandadi. “We also acquired a product from Vapor Tech which speeds up evaporation called V10, in late 2005. We have now a number of tools that speed up the synthetic work flow of drug discovery chemistry.” She adds, “The evaporation product is the only one that can evaporate high-boiling solvents very rapidly, taking from an hour-and-a-half down to 45 minutes.”
The fourth way
Researchers are looking to a fourth way of doing drug discovery, which is neither medicinal chemistry, nor combinatorial chemistry, nor even a parallel synthesis method. So it appears that other strategies for drug discovery are evolving.
Some scientists are going back to nature to cull new compounds, says Desai, whose lab collaborates with a small biotech company in Cleveland. After deducing the natural molecule’s structure and workings, chemists make subtle modifications to come up with analogues, he says.
Alternatively, modern chemists design molecules in silico via computational modeling. “We can take the structure of a protein, and make a library in the combinatorial way. Let’s say you can screen 50,000 molecules in silico, you could end up with 1,000 to 1,500 hits,” said Desai, who believes it will be about five years before drugs will be developed using these approaches.
About the Author
Otrompke is a freelance writer based in Chicago.
This article was published in Drug Discovery & Development magazine: Vol. 10, No. 2, February, 2007, pp. 44-45.
Filed Under: Drug Discovery