Nano Science and Technology Institute

Techniques for Rapid Drug Discovery Now Focusing on Nanoscience Research

Ron Zuckermann, lead scientist for Lawrence Berkeley National Lab’s Molecular Foundry Biological Nanostructures Facility, is taking the same techniques drug companies use to discover drugs to help nanoscientists cut the cost and shorten the time for their hunt for useful nano-compounds.
Dr. Zuckermann knows a lot about that proven drug-discovery process, dubbed combinatorial chemistry – he helped invent the process more than a decade ago. Before coming to the Molecular Foundry, Dr. Zuckermann worked for the biotechnology industry, and was one of the creators of the combinatorial chemistry techniques, whereby researchers create and test thousands (and in some cases millions) of compounds for just the right properties. His current LBNL work is sponsored by the Department of Energy, and is available for universities and private research arms to participate in.

“For many in nano-research, investigators start with a hypothesis and then create and test a few, or maybe a few dozen [candidate] nano-specimens. And, that can be very expensive and time-consuming,” Dr. Zuckermann said. “With our approach, we can create hundreds or thousands of times as many candidates, using very low-cost materials in very little time, and simply test all of them for the result we want.”

Nano World News talks to Dr. Zuckermann about ways his approach could improve productivity for nanoscientists.

NWN: Can you provide a simple overview of ‘combinatorial chemistry’ and how it could help nanoresearchers?

Zuckermann: Combinatorial chemistry looks to mimic the way nature makes nanostructures. Look at RNA and proteins. They are bio-polymers, made from a linear sequence of monomers. The unique thing is they are sequence specific, whereas manmade polymers typically repeat the same smaller units over and over again. Combinatorial chemistry aims to let researchers build lots of sequence-specific oligomeric molecules from very simple building blocks very efficiently.

Biology is our inspiration here. In our bodies, we have billions of antibodies floating around all the time, and a few of them, just by virtue of their unique sequence, will recognize a foreign virus, for example. Large populations of chemical or biological diversity can be an extremely powerful resource of materials with new properties. Chemists, particularly in the pharmaceutical industry, have been emulating this biological concept for a long time, often using combinatorial chemistry to discover new drug candidates.

NWN: Why come to LBNL?

Zuckermann: Because the Molecular Foundry is a user facility, our tools and techniques are openly available to the research community. It is truly exciting to be in a position where I can interact with researchers from around the world and see how we can impact cutting-edge research in so many different ways.

NWN: And, so briefly, how does combinatorial chemistry work in the lab?

Zuckermann: It’s all based on sequence-specific synthesis. Chemists have spent a lot of time working on efficient ways to synthesize materials to add one building block at a time into specific sequences. The idea is that if you have control over [molecular] sequences, you can fold the backbone up into defined shapes and structures, such as a helix or sheet. We are essentially mimicking the way nature creates nanostructures: arrange monomers into a specific sequence and fold them into defined secondary structures, which can further assemble into defined 3D structures.

The exciting part comes when you do this for synthetic molecules that have improved properties over nature’s biopolymers (like better stability and increased chemical diversity). For instance, we make “peptoids,” which are close structurally to peptides, but offer many advantages. We devised this chemistry to use inexpensive, readily-available building blocks (primary amines). There are literally thousands of these commercially available. We built custom robots to assemble these building blocks into vast libraries – fully automatically. Our chemistry allows one to incorporate an almost unlimited repertoire of chemical groups into our oligomers. This allows us to design custom-made molecules tailored to a wide variety of projects.

NWN: How are you changing the way combinatorial chemistry is used?

Zuckermann: Combinatorial chemistry comes from the drug discovery world: biotech and pharmaceutical. It is the idea of making different combinations of chemical building blocks to look for new drugs, and it lets us screen a 100,000 compounds (combinations) or more for the biological activity we want. Combinatorial chemistry is so powerful, we could almost make compounds (combinations) at random, just to test for the activity or property we’re looking for.

So, we are applying that paradigm to looking for new nanostructures and functions. Since the chemistry works so well, we don’t have to design a single target structure. Our attitude is let’s make all possible molecules, or say a million 50-mers. [50 building blocks in a row, the size of a protein.] We can make all of these and evaluate them independently for whether they are active or not.

NWN: What would this technique be useful for?

Zuckermann: This kind of thing could be useful for self-assembled patterns on surfaces or maybe for lithography to etch patterns. Like a material that forms regularly-spaced pores, for example. So, we’re definitely interested in that. But, we want to add bio-recognition, so that our materials can interact productively with biological systems.

The idea of having bio-mimetic materials that can self-assemble will be of interest to the biomedical community as well. People doing drug delivery, protein delivery, vaccines and diagnostics. Many problems in these areas involve the formation of self-assembled complexes. We can provide materials and discovery tools to find new formulations that might help a drug be delivered more effectively, for example.

NWN: How would that work in a real nanoresearch project?

Zuckermann: We are using these techniques to build a completely artificial enzyme. This is a material made from a (non-natural) synthetic peptoid. We want this polymer to fold up in a certain way and catalyze a specific chemical reaction. That hasn’t been done yet, by the way. We hope to find new industrial catalysts that will perform highly specific tasks, but have much improved performance and durability.

But, in this example, the idea is let’s make 1,000,000 molecules in parallel using robots and combinatorial chemistry - these tools exist in our facility today. But how do you find a needle in a haystack to find one folded up in the correct way to perform a task you want to do? That has to be done by screening, where you measure the activities of all of them and see how well they are doing and pick the ones doing the best job. We are currently developing these methods, and adapting existing methods to solve problems in nanoscience.

NWH: Do you think chemists will have better luck with combinatorial chemistry working at the nanoscale, with things like shape, charge, etc?

Zuckermann: I’d almost flip that question around, in fact. It turns out, organic chemists, and the drug industry in particular, is very good at controlling structure at the <1 nanometer scale. In fact, most pharmaceutical work focuses on just single molecules that contain only dozens of atoms.

The combinatorial chemistry I have developed is one of the few ways we can make and test molecules on a 10-fold larger scale. We are now performing organic synthesis on the 1-10 nanometer scale. Now we are in the size range of small proteins (1-10 nm), rather than just smaller molecules. Control of soft matter structure in this size just hasn’t been done very well, at least with synthetic organic molecules.

NWN: How does a research facility get involved?

Zuckermann: We want to hear from researchers, as our tools and expertise is open to researchers from academia – both established labs as well as new labs, and private firms – both large and small. The ability to speed discovery of nanoscale materials is a main focus of our efforts. The molecules we are making are tough and robust, and can be incorporated into devices, and they will last for a while. Natural molecules, or proteins, won’t last too long. It’s a new frontier - a lot of things can be done.

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