Spot the difference: NMR technique for drug design

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  • Published: Oct 15, 2017
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Spot the difference: NMR technique for drug design


 Differential Epitope Mapping (D2O/H2O) of 2,7-anhydro-Neu5Ac in complex with RgNanH-GH33 Credit: Angulo/Angewandte Chemie)

A powerful new NMR technique DiffErential EPitope mapping by STD (saturation transfer difference) NMR spectroscopy (DEEP-STD NMR) is being used by researchers in the UK to reveal the nature of the contact between ligand and protein target with a view to developing new pharmaceuticals with fewer side-effects.

The majority of pharmaceuticals work by binding to a particular site on a protein target, whether enzyme, receptor, or other type of protein. They usually then modulate the activity of the protein by causing a conformational change, stimulating, or blocking it in some way. Of course, drugs are usually not quite as specific in their activity as their designers would like and other proteins unrelated to the disease or disorder being treated might affected too. This is often the underlying cause of many side effects. To discover new pharmaceuticals that have fewer detrimental effects, drug designers need to know more about the interaction between ligand the protein so that the pharmaceutical ligand might be designed to be more highly targeted towards its protein. Unfortunately, many of the current techniques used to investigate ligand-protein interactions can only offer part of the picture. They can give details about which parts of the drug is important to the interaction and, in some cases, the overall structure of the protein but rarely the whole atom by atom, bond by bond picture.

Ligand approach

Now, researchers at the University of East Anglia have now developed a new approach that can reveal the other side of this designer's jigsaw puzzle: the specific parts of a protein target that interact with the drug. They have adapted ligand-based nuclear magnetic resonance (NMR) spectroscopy to reveal which amino acids in the protein are involved in binding to a drug. Their approach was able to extract useful information without prior labelling of the protein, something that is almost a prerequisite for many of the other techniques used.

"Designing novel drugs is a bit like finding the proper piece that fits into a jigsaw puzzle," explains team leader Jesus Angulo. "It is not just the shape but also graphical content on the piece that must match the surrounding picture. Our novel approach allows us to now find the exact piece that matches the complementary shape and graphical content in a protein binding site."Angulo and his colleagues describe details of how they have used DEEP-STD NMR in the journal Angewandte Chemie.

STD-NMR exploits the nuclear Overhauser effect and makes it possible to characterize the hydrogen atoms in the ligand that are closest to the protein when the ligand binds. Angulo and his colleagues have now used the approach and irradiated the protein at different frequencies to excite different amino acids in the protein chain to extract additional information. This, they explain, allowed them to unpick which amino acids in the protein’s binding site are directly in contact with the drug.

Trigger happy

Fundamentally, this allowed them to look more closely at the drug to determine which are the most important parts of the protein that are being targeted. Additionally, the use of heavy water in the NMR experiments gives them additional clues. Angulo worked with researchers from the Quadram Institute in Norwich to have demonstrated proof of principle for their method on two well-known proteins - the enzyme intramolecular trans-sialidase, which is produced by a bacterium found in the human gut, and a protein subunit of the cholera toxin. "Our new method gives researchers a powerful tool to indirectly understand the architecture of the protein binding pocket," Angulo explains. "This will allow them to determine what are the best chemical requirements for a drug to interact specifically with a given protein receptor. This could to lead to stronger and more selective drug candidates, while lower amounts would be needed to trigger the desired effect."

Related Links

Angew Chem 2017, online: "DiffErential EPitope mapping by STD NMR spectroscopy (DEEP-STD NMR) to reveal the nature of protein-ligand contacts"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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