When I saw the press release on this research (here it is), I wasn't sure I could get a column of it, so I caught the corner of the "big molecule". Now that it's in print, I'm still not sure I can make a column of it. But it's Tuesday – I had to file something!
This is an embarrassing admission for a sci-fi enthusiast, but it never occurred to me until recently that molecules can have different sizes.
I know that different molecules can contain a very different number of atoms, but somehow it never affected my impression of how big they are. I imagine I imagined that all the atoms were smoked together in a very small point that really had no dimensions.
That image, which could help explain my chemistry degrees, was gently but firmly set aside by Harish Vashisth, assistant professor of chemical engineering at the UNH, when I talked to him about recent research that was aimed at agricultural pests known as nematodes or nematodes.
Vashisth is very concerned about the molecular size because his laboratory specializes in the study of how small molecule drugs can be used.
"A very large molecule cannot cross the membrane and attack something inside the cell. A small molecule can sneak in through the spaces in the wall and go inside the cell and find a small space on the target" , said Vashisth. "It is very strategic and extremely important to be able to design smaller molecules to attack larger molecules and enter the cell."
If you don't like it Mission Impossible image of the good boy who sneaks into the fortified enclave, how about a Star Wars image of the X-wing fighter finding the weak spot on the surface of the Death Star.
"Large molecules can be like spheres," Vashisth said. "There are hills and valleys on the surface – some places that are deeper, others that aren't. … The smaller molecules can go and adapt in smaller spaces that a large molecule cannot."
The goal is not to blow up the big molecule, but only to change what it does.
The large molecules in question are often proteins and enzymes that, obviously, do much of the vital work. If you can find small molecules that alter the action of proteins and enzymes, then you can do all sorts of things. You could create specialized medicines for us humans or, as in the case we are talking about, you could create pesticides that are more respectful of the environment.
Pesticides are necessary because nemadots are a big problem in agriculture. They are a class of tiny worms that can infest the roots of many crops and cause literally billions of dollars in damage.
UNH has just announced a breakthrough is the understanding of phosphodiesterase or PDE enzymes in nematodes, to better understand how to create PDE inhibitors – small molecules that could interfere with those large enzyme molecules and do things that make it impossible for nematodes to find food.
Trying to determine how all the PDE"Working and then deciding what would be a good goal for interruption is a huge task that could take decades," said Vashisth. Thus UNH pursued a shortcut, leading to a recent publication in the online journal PLOS ONE and a patent-pending discovery (available for licensing through UNHInnovation, the university notes).
"Many of these large molecules, such as enzymes, are found among species – found in mice, found in humans" and in nematodes, he said. "Because we know how the human enzyme works, we use it as a model."
They superimposed the genetic specifications of the nematodes on the "I had a three-dimensional model as a first hypothesis" model. These models are mostly in computers, but they are also 3D printed to help with analysis.
"There are drugs on the market that attack and block human enzymes. … We took human drugs to see if they fit in the same place, we physically took the model and tested it," he said.
In the end, he said, they found a static model that worked, bypassing years of effort. But there is still a lot to do.
First, the molecules move. A static model doesn't tell you everything you know – this is where computer modeling, using various UNH supercomputers to run simulations, is crucial.
"This has captured the physics of how the smaller molecule and larger molecule talk to each other. We let the model evolve and watch what happens. … This gives us an idea of the coming years on how to use these information to design new drugs that are more effective, "he said.
Designing this new drug to combat nematodes in search of roots requires research through the vast library of available drugs to see which one fits the static model. This is where modeling really comes into play.
"Perhaps for example let's say 100,000 we could find, say, 50 that bind to our proteins. So we can build dynamic models for each of them and classify them on which one is more effective than others. Once you have a good ranking you could go with your top 5 and try an experiment – inject into the nematode and see if it kills the bug somehow, "he said.
In other words, even with the shortcut, the years of work are ahead. But at least progress is feasible, while the creation of experiments to test hundreds or thousands of potential drugs would not be.
Other researchers involved in this work include Prof. Rick Cote, a researcher with the New Hampshire Agricultural Experiment Station; Kevin Schuster, doctoral student in biochemistry; MohammadjavadMohammadi, doctoral student in chemical engineering; Karyn Cahill and Suzanne Matte, former research staff; and Alexis Maillet, a university student in biomedical sciences.