Nav: Home

Figuring out the 3-D shape of molecules with a push of a button

June 19, 2017

An international team of researchers led by Carnegie Mellon University chemist Roberto R. Gil and Universidade Federal de Pernambuco chemist Armando Navarro-Vázquez has developed a program that automates the process of figuring out a molecule's three-dimensional structure. The technique, described in a paper in Angewandte Chemie, compresses a process that usually takes days into minutes and could shorten the pipeline of drug discovery by reducing human error.

Figuring out the chemical structure of a molecule from scratch is an essential part of researching chemicals that come from nature, or "natural products." For substances with possible pharmaceutical use, that structure can reveal how the substance might interact with the human body.

"If the molecule is going to be a drug, you need to know the shape of the molecule to know how it's going to interact with a receptor," says Gil, a professor in the Department of Chemistry at Carnegie Mellon's Mellon College of Science.

The first step in determining a molecule's structure is determining its atomic building blocks, followed by finding out its two-dimensional structure, which shows how each atom is connected to each other. While some atomic bonds are stiff, others can rotate around a joint, making it possible for molecules with the same components and two-dimensional (2D) structures to have different three-dimensional (3D) shapes.

Small differences in shape can translate into large changes in how drugs act in the body. For instance, rotating one bond in the popular pain reliever ibuprofen makes it completely inactive. Similarly, starch and cellulose share the same 2D structure but have different 3D shapes. That difference is the reason why humans can digest grains and not wood.

Gil and Navarro-Vázquez have been working for eight years to simplify the process of finding and sorting through the possible 3D shapes for any given 2D structure. And with the laboratory tools for gathering data on a molecule's 3D structure becoming more widespread and available, the time was right to develop a method to automate and streamline the process.

The researchers created a program, written in the Python programming language, that makes use of Residual Dipolar Coupling (RDC) information, a measure of the distance between atoms extending from rotating bonds. Fed with data about a given molecule from RDC experiments, the program generates possible ways that the molecule can exist in three dimensions, and picks the most likely option.

The technique is most effective at tackling the 3D structure of organic molecules that are small-to-medium sized, and relatively rigid, with carbon atoms packed into rings rather than linked into long, bendy chains. The team tested their program on six such molecules, including naltrexone, a medication used to block the effects of opioids, and strychnine, a pesticide.

First, they determined the 2D structure of each molecule using a computer-assisted structure elucidation (CASE) program, aided by a collaboration with Clemens Anklin, vice-president for NMR applications and training at Bruker Corporation. They fed that information, along with RDC data about the molecule, into their new program. In each case, their program was able to pick out the correct 3D structure.

"You push a button, and with little human or no human intervention, you go from 2D to 3D structure in one shot," says Gil.

But just as important as the program's speed is its thoroughness.

"The amount of natural products that are wrongly reported, where the reported structure does not correspond to the real structure, is really large," says Navarro-Vázquez, a chemistry professor at Universidade Federal de Pernambuco in Brazil. This program could be a valuable way to check for possible structures that researchers might otherwise miss, helping them avoid their own inherent biases.

Gil traces his vision of this process back to his time as a graduate student and a conversation with a mentor 30 years ago about the idea that chemists could one day put a substance into a machine and see its structure with the push of a button. Soon, he hopes, programs like his and Navarro-Vázquez's creation will integrate the earlier steps of the process, bringing that vision even closer to reality.

"We are very close," says Gil. "This is the dream of any chemist."
-end-
The study was supported by the National Science Foundation (CHE-0130903, CHE-1039870, and CHE-1111684) and Fundação do Amparo a Ciência e Tecnologia (APQ-0507-1.06/15).

Carnegie Mellon University

Related Chemistry Articles:

Better chemistry through tiny antennae
A research team at The University of Tokyo has developed a new method for actively controlling the breaking of chemical bonds by shining infrared lasers on tiny antennae.
Chemistry in motion
For the first time, researchers have managed to view previously inaccessible details of certain chemical processes.
Researchers enrich silver chemistry
Researchers from Russia and Saudi Arabia have proposed an efficient method for obtaining fundamental data necessary for understanding chemical and physical processes involving substances in the gaseous state.
The chemistry behind kibble (video)
Have you ever thought about how strange it is that dogs eat these dry, weird-smelling bits of food for their entire lives and never get sick of them?
Top 10 chemistry start-ups
Starting a new chemistry-based company is one part discovery, one part risk.
Biomimetic chemistry: Carbohydrate capture
LMU chemists have designed and synthesized a helical molecule that specifically recognizes and binds to a disaccharide consisting of two five-carbon sugar units.
Reining in soil's nitrogen chemistry
The compound urea is currently the most popular nitrogen soil fertilizer.
Taking a closer look at 'electrifying' chemistry
With the increasing availability of electrical energy from renewable sources, it will be possible in the future to drive many chemical processes using an electric current.
The changing chemistry of the Amazonian atmosphere
Researchers have been debating whether nitrogen oxides (NOx) can affect levels of OH radicals in a pristine atmosphere but quantifying that relationship has been difficult.
The chemistry of Hollywood bloodbaths (video)
Fake blood is a staple of the Halloween horror film experience, but there's no one recipe to suit every filmmaker's needs.
More Chemistry News and Chemistry Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

Risk
Why do we revere risk-takers, even when their actions terrify us? Why are some better at taking risks than others? This hour, TED speakers explore the alluring, dangerous, and calculated sides of risk. Guests include professional rock climber Alex Honnold, economist Mariana Mazzucato, psychology researcher Kashfia Rahman, structural engineer and bridge designer Ian Firth, and risk intelligence expert Dylan Evans.
Now Playing: Science for the People

#540 Specialize? Or Generalize?
Ever been called a "jack of all trades, master of none"? The world loves to elevate specialists, people who drill deep into a single topic. Those people are great. But there's a place for generalists too, argues David Epstein. Jacks of all trades are often more successful than specialists. And he's got science to back it up. We talk with Epstein about his latest book, "Range: Why Generalists Triumph in a Specialized World".
Now Playing: Radiolab

Dolly Parton's America: Neon Moss
Today on Radiolab, we're bringing you the fourth episode of Jad's special series, Dolly Parton's America. In this episode, Jad goes back up the mountain to visit Dolly's actual Tennessee mountain home, where she tells stories about her first trips out of the holler. Back on the mountaintop, standing under the rain by the Little Pigeon River, the trip triggers memories of Jad's first visit to his father's childhood home, and opens the gateway to dizzying stories of music and migration. Support Radiolab today at Radiolab.org/donate.