Leeds University researchers open up route to cheaper and more effective drug discovery

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Researchers at the University of Leeds have developed a way to reduce the costly and time-consuming search for new drug molecules, by moving beyond simple structure-based design to factoring in the dynamics of drug–to–ligand interactions.

Almost everything in the body – including diseases – is a result of a protein binding with another molecule, known as a ligand. Drug treatments work by blocking this process with another molecule, which takes the place of the natural ligand. Most companies still rely heavily on high throughput screening of thousands possible candidates to find the right fit, a process which is both time-consuming and costly.

“In the past, scientists have tended to look at the protein–ligand interaction like a lock and key – as if the protein is a fixed shape into which the ligand fits,” says Professor Steve Homans of the Faculty of Biological Sciences.

“In reality, it’s more like a hand and glove, where you can’t see the real shape of the glove until the hand is inside it. Proteins are very dynamic and the movement that takes place during the interaction with the ligand is an important factor in the binding process.”

Another factor in the binding process is the action of water molecules in the solution which surrounds the protein. “The problem in drug design is knowing to what extent all these factors are influencing the binding process,” says Homans.

Working from nuclear magnetic resonance data, Homans created a computer simulation of a dynamic protein interaction and used it to develop an algorithm for measuring the relative contribution of each factor to a protein interaction. If the method holds true for all proteins it will be possible to directly identify a ligand that is not only a perfect fit but has a greater affinity for the target than its natural ligand.

Homans now plans to test this process using a real target protein for disease – HIV. “Scientists have known for many years that protein, ligand and water all play a part in the protein interaction, but there has always been intense debate about the contribution each makes. We believe we’ve finally answered that question and opened up a potentially cheaper and more effective avenue for drug design,” he said.