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Side effects on every side
ATLANTA—A recent study out of the Georgia Institute of Technology has revealed that side effects, the bane of all drugs, might actually be unavoidable. By comparing computer-generated proteins with natural proteins, researchers found that the number of unique pockets where small-molecule compounds can bind to proteins is fairly limited.
It turns out that there may be as few as 500 unique protein pocket configurations that provide binding sites for small-molecule ligands, which could explain why side effects occur in most drugs; with so few unique configurations, chances are high that regardless of the composition of a small molecule, it will bind with unintended targets as well as its intended binding site.
"This is the first time that it has been shown that side effects of drugs are an inherent, fundamental property of proteins rather than a property that can be controlled for in the design," Jeffrey Skolnick, a professor in the School of Biology and director of the Center for the Study of Systems Biology at Georgia Tech, said in a press release. "The physics involved is more important than had been generally appreciated."
Skolnick, along with collaborator Mu Gao, produced a set of artificial proteins through computer simulations, which were folded according to the laws of physics rather than evolutionary optimization. They compared the pairs of binding pockets and statistical significance of their structural overlap in both the generated proteins and natural proteins, and found that the artificial pockets had corresponding pockets on natural proteins. The modeling was done with a representative covering of all protein types.
"You could have the same or very similar pockets on the same protein, the same pockets on similar proteins and the same pockets on completely dissimilar proteins that have no evolutionary relationship. In proteins that are related evolutionarily or that have similar structures, you could have very dissimilar pockets," Skolnick explained. "This helps explain why we see unintended effects of drugs, and opens up a new paradigm for how one has to think about discovering drugs."
Proteins' binding pockets are formed by the secondary nature of amino acids, which is directed by hydrogen bonding and results in the formation of similar pockets on many different proteins, even unrelated ones.
If the geometry of these proteins and the location of their binding pockets could be modeled, drug developers could have new insight into how small-molecule drugs need to be shaped in order to avoid the worst possible side effects, and Skolnick says they are already working on such modeling.
"You can produce models of acceptable quality where you can do virtual screening for effectively three-quarters of any proteome," he says.
It is possible to look through proteins and construct a network, "like a promiscuity index," says Skolnick, to get a rough idea of the sites at which a molecule might bind. Along that same line, once these pockets are better understood and identified, it could also be possible to shape a small molecule in order to choose which side effects will result, shaping it to avoid binding with off-target sites associated with important biological processes.
"The key next question is to try to move this to the next level, to try to correlate patterns and targets with physiological response to be predictive…you bind and would like to be able to predict or suggest with a better than reasonable probability, which is probably realistic at this point, that this collection of targets are likely to have a positive physiological response," says Skolnick, adding that "one has to think of it as a network response rather than a single molecule response."
"How do you pick a target or the targets that are going to give you the response that you want? That's where we're heading," he adds.