In a paper published this week in Angewandte Chemie, Professor Steve Homans from Leeds’ Faculty of Biological Sciences explains his method for getting exactly the right molecule first time, by looking not just at the physical shape required to fit the target protein but also at the complex dynamics of the interaction.
Almost everything in the body – including diseases – is a result of a protein binding with another molecule, known as a ligand. Most drug treatments work by blocking this process with another molecule, which takes the place of the natural ligand. Because the binding process is still only partly understood, drug companies currently have to search through millions of possible candidates to find the right ‘fit’, a process which is both time-consuming and costly.
Professor Homans explains: “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. 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 key factor is the action of the 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.”
For the first time, Professor Homans’ team have found a way to put a number on how important these different factors are to a protein interaction. They believe that – if their method holds true for all proteins – it will be possible to compute these figures to identify a ligand that is a perfect fit. Ideally, they want to find or create one which will bind more tightly to the protein than its natural counterpart and so act as an effective treatment by fully blocking the target interaction.
The research was done using a multidisciplinary approach including nuclear magnetic resonance (NMR) and protein crystallography. From the NMR data, the team were able to create a computer simulation of the dynamic protein interaction. Professor 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.
Abigail Chard | alfa
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