Roughly 40 percent of all medications act on cells' G protein-coupled receptors. One of these receptors, beta 2 adrenergic receptor site (B2AR), naturally transforms between two base configurations; knowing the precise location of each of approximately 4,000 atoms is crucial for ensuring a snug fit between it and the drug.
Now, researchers at Stanford and Google have conducted an unprecedented, atom-scale simulation of the receptor site's transformation, a feat that could have significant impact on drug design. This is the first scientific project to be completed using Google Exacycle's cloud computing platform, which allows scientists to crunch big data on Google's servers during periods of low network demand.
The study was published in the January issue of Nature Chemistry.
As a type of GPCR, the B2AR is a molecule that sits within the membrane of most cells. Various molecules in the body interact with the receptor's exterior, like two hands shaking, to trigger an action inside the cell.
"GPCRs are the gateway between the outside of the cell and the inside," said co-author Vijay Pande, PhD, professor of chemistry and a senior author of the study. "They're so important for biology, and they're a natural, existing signaling pathway for drugs to tap into."
Lead authors of the study were former postdoctoral scholar Kai Kohlhoff, PhD, and current postdoctoral scholars Diwakar Shukla, PhD, and Morgan Lawrenz, PhD.
Roughly half of all known drugs—including pharmaceuticals and naturally occuring molecules, such as caffeine —target some GPCR, and many new medications are being designed with these receptor sites in mind. Brian Kobilka, professor of molecular and cellular physiology at Stanford, was awarded the 2012 Nobel Prize in Chemistry for his role in discovering and understanding GPCRs.
Traditionally, maps that detail each atom of GPCRs and other receptors are created through a technique called X-ray crystallography. The technique is industry standard, but it can only visualize a molecule in its resting state; receptors naturally change configurations, and their intermediate forms might also have medical potential.
When developing a drug, scientists will often run a computer program, known as a docking program, that predicts how well the atomic structure of a proposed drug will fit into the known receptor.
In the case of GPCRs, for example, the X-ray crystallography techniques have detailed their "on" and "off" configurations; many medications have been specifically designed to fit into these sites. Scientists expect, however, that other fruitful configurations exist. Many drugs engage with GPCR sites, even though computational models suggest that they don't fit either of the two defined reaction site configurations.