A new study of both computer-created and natural proteins suggests that the number of unique pockets -- sites where small molecule¹ pharmaceutical² compounds can bind³ to proteins -- is surprisingly small, meaning drug side effects may be impossible to avoid. The study also found that the fundamental biochemical processes needed for life could have been enabled by the simple physics of protein folding. Studying a set of artificial proteins and comparing them to natural proteins, researchers at the Georgia Institute of Technology have concluded that there may be no more than about 500 unique protein pocket configurations⁴ that serve as binding⁵ sites for small molecule ligands（配体）. Therefore, the likelihood that a molecule intended for one protein target will also bind with an unintended target is significant, said Jeffrey Skolnick a professor in the School of Biology at Georgia Tech.

 

"Our study provides a rationalization for why a lot of drugs have significant side effects -- because that is intrinsic（本质的） to the process," said Skolnick. "There are only a relatively⁶ small number of different ligand binding pockets. The likelihood of having geometry in an amino acid composition that will bind the same ligand turns out to be much higher than anyone would have anticipated. This means that the idea that a small molecule could have just one protein target can't be supported."

 

Research on the binding pockets was scheduled to be published May 20 in the early online edition of the journal Proceedings⁷ of the National Academy of Sciences. The research was supported by the National Institutes of Health (NIH).

 

Skolnick and collaborator⁸ Mu Gao have been studying the effects of physics on the activity of protein binding and contrasting the original conditions created by the folding of amino acid residues⁹ against the role played by evolution in optimizing¹⁰ the process.

 

"The basic physics of the system provides the mechanism¹¹ for molecules¹² to bind to proteins," said Skolnick, who is director of the Center for the Study of Systems Biology at Georgia Tech. "You don't need evolution to have a system that works on at least a low level. In other words, proteins are inherently capable of engaging in biochemical function without evolution's selection. Beyond unintended drug effects, this has a lot of implications for the biochemical component¹³ of the origins of life."

 

Binding pockets on proteins are formed by the underlying¹⁴ secondary structure of the amino acids, which is directed by hydrogen bonding in the chemistry. That allows formation of similar pockets on many different proteins, even those that are not directly related to one another.

 

"You could have the same or very similar pockets on the same protein, the same pockets on similar proteins, the same pockets on completely dissimilar proteins that have no evolutionary¹⁵ relationship. In proteins that are related evolutionarily or that have similar structures, you could have very dissimilar pockets," said Skolnick, who is also a Georgia Research Alliance Eminent¹⁶ Scholar. "This helps explain why we see unintended effects of drugs, and opens up a new paradigm¹⁷ for how one has to think about discovering drugs."

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