Nuclear magnetic resonance aids in drug design

May 19, 2010

A new study by a team of researchers led by Jeffrey Peng, assistant professor of chemistry and biochemistry at the University of Notre Dame, is using Nuclear Magnetic Resonance (NMR), to move drug design into groundbreaking consideration of the dynamic flexibility of drugs and their targets.

The research, which was published by the , contributes to the growing attention given toward the shape-shifting movement of molecules, a feature that potentially could help drug designers overcome issues of resistance, transportation of drugs to targets and oral bioavailability.

"The new focus is that it's not enough just to look at the protein motion," Peng said. "Of course, we've studied protein motions for some time, as many disease-related proteins are flexible. But we've also realized that in order to impact , we also have to look at the candidate drug molecule that is being designed, that is, the 'ligand.' It can move too."

Drug design involves iterative changes of a ligand to optimize its drug-like properties, which include, among other issues, the ability to cross biological membranes and bind specifically to a drug-target, usually a protein. The rules for doing this are well-established for rigid ligands, but much less so for flexible ligands, which turn out to be common starting points for many drug-targets.

"Understanding that lets us predict how flexibility can affect drug-like properties, and how that flexibility should be manipulated in drug design is still elusive," Peng said.

"We need experimental methods that can tell us, systematically, how architectural changes in the candidate drug molecule can change its flexibility relevant for drug-like properties. These methods would benefit not just one particular kind of disease but basically drug design in general," including therapies for cancer, AIDS and MRSA.

"The paper is a beginning of how to systematically understand how we should make ligand molecules, candidate drug molecules, floppy or not floppy, in order to best interfere with the target protein. For example, we can test the idea that some residual 'floppiness' in a drug may help it co-adapt with a protein target site that 'morphs' over time, on account of drug-resistant mutations. We can also study how drug 'floppiness' can affect its ability to cross biological membranes and reach its protein target."

Peng, who worked as a biophysicist at a pharmaceutical company for 10 years before he came to Notre Dame, said the study of flexibility-activity relationships (FARs) adds another dimension to the longstanding structure-activity relationships (SARs) that scientists have studied. Addressing the dynamism of both the target molecule and the drug molecule can provide important resources for drug designers.

"If you could know, atom by atom, which parts have to move and which do not have to move to bind to a target protein, that's information a chemist can use," he says. "They can change the ligand as chemists do, repeat the activity assay, and see if it has improved."

Explore further: New chip promising for tumor-targeting research

add to favorites email to friend print save as pdf

Related Stories

Intrinsic changes in protein shape influence drug binding

Aug 19, 2009

Computational biologists at the University of Pittsburgh School of Medicine have shown that proteins have an intrinsic ability to change shape, and this is required for their biological activity. This shape-changing also ...

New computational technique can predict drug side effects

Dec 11, 2007

Early identification of adverse effects of drugs before they are tested in humans is crucial in developing new therapeutics, as unexpected effects account for a third of all drug failures during the development process.

Researchers develop more computer-aided drug design

Mar 10, 2008

Researchers in Germany report an advance toward the much awaited era in which scientists will discover and design drugs for cancer, arthritis, AIDS and other diseases almost entirely on the computer, instead of relying on ...

Can cancer drugs combine forces?

Aug 16, 2007

Individuals with chronic myeloid leukemia (CML) are treated first with a drug known as imatinib (Gleevec), which targets the protein known to cause the cancer (BCR-ABL). If their disease returns, because BCR-ABL mutants emerge ...

Recommended for you

New chip promising for tumor-targeting research

9 hours ago

(Phys.org) —Researchers have developed a chip capable of simulating a tumor's "microenvironment" and plan to use the new system to test the effectiveness of nanoparticles and drugs that target cancer.

New star-shaped molecule breakthrough

15 hours ago

(Phys.org) —Scientists at The University of Manchester have generated a new star-shaped molecule made up of interlocking rings, which is the most complex of its kind ever created.

A refined approach to proteins at low resolution

Sep 19, 2014

Membrane proteins and large protein complexes are notoriously difficult to study with X-ray crystallography, not least because they are often very difficult, if not impossible, to crystallize, but also because ...

User comments : 0