Drug side effects may be an inevitable consequence of the physical properties of proteins and the molecules that bind to them, according to a new study published online in Proceedings of the National Academy of Sciences. In addition to advancing pharmaceutical research, the biochemical processes uncovered in the study may have further implications for the origin of life on earth, the researchers say.
It’s a truism of modern life that the list of side effects on a prescription bottle will be longer than the list of symptoms the medication addresses. The new study suggests an explanation. Using a computer simulation to compare naturally occurring and artificial proteins, researchers from the Georgia Institute of Technology found that proteins contain only a limited number of sites where pharmaceutical compounds can bind, so many molecules inadvertently latch on to unintended targets, triggering the unwanted effects.
“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,” lead author Jeffrey Skolnick said in a statement. “The physics involved is more important than had been generally appreciated.”
According to one theory, proteins were initially spherical objects, and the pockets were carved out during evolutionary selection. Another theory suggests that the pockets were naturally occurring structural defects that encouraged biochemical interactions even before evolution took hold, an idea dating back to 1976 and supported by other studies within the past five years.
To test the theories, the researchers used a computer model to produce a series of proteins constructed in accordance with the laws of physics. Using an algorithm to evaluate the various protein-pocket combinations, they attempted to quantify the number of known binding sites and assess the relationship between pocket structures and protein geometry.
From their analysis, the researchers concluded that there are no more than approximately 500 unique types of pocket configurations that allow molecules to bind to them. They also found that the pocket structures on artificial proteins mirrored the pocket structures found on naturally occurring proteins, suggesting that the protein’s folds — a function of physics — largely determine pocket structure. And while similar pockets could occur on the same protein, similar proteins, or unrelated proteins, dissimilar pockets also occurred on structurally and evolutionarily related proteins.
The study supports the theory that pockets are a fundamental part of protein structures that occur irrespective of their function. In light of their findings, the researchers suggest that early protein structures facilitated constant random interactions with molecules, which evolution then fine-tuned.
The research has further significance for how we design new pharmaceuticals. In their paper, the scientists write that their research “implies that the notion of one-molecule one-target that underlies how many aspects of drug discovery is likely incorrect.” They argue that the old understanding of how drugs work underestimates the probability that molecules and proteins will interact based on coincidental similarities. Other recent studies from 2011 and 2012 also questioned the old model of pharmaceutical development and highlighted the “promiscuous” nature of protein-binding molecules.
While the study suggests that side effects can never be completely eliminated, there is a bright side – it also proposes a way to minimize the side effects that will inevitably occur. To break through the “biological noise,” of molecule-protein interactions, drug developers must learn more about the locations and structures of available pockets, the researchers say. By gathering this information, we may be able to design drugs that direct the unintended binding away from critical proteins and onto lesser ones. Considering the large number of people who neglect their vital medications over concerns about side effects, new research on this line can’t come fast enough.