Medicine has been important to humans since our earliest days, but for the majority of our history, we’ve had very little idea of how medicine works. We used to attribute medicinal effects to magic or to balancing the fluids of the body (bloodletting, anyone?), but thankfully we’ve come a long way since then. With the development of tools to understand the mechanisms of our bodies’ inner workings, let’s take a brief glimpse at the tiny, wiggly world of molecular medicine.
Locked Or Unlocked
Drugs are ultimately just small molecules that you can think of as “keys” that are targeted to work on specific cellular “locks”. Proteins are one of the building blocks of cells and make up our cellular locks. How keys specifically fit with their locks determines the effect they have on our bodies. The action of the keys (small molecule/drug) fitting into the locks (cellular proteins) causes them to physically change their shape. These small changes can have a big effect on the cell itself. The keys turn these locks on or off by changing their physical shape, which in turn sends a signal through the rest of the cell, causing a larger effect. Just as how turning a key in a car quickly gets the engine running from such a small movement, the event of a small molecule fitting into a protein and causing an effect happens very rapidly. This is called a signaling event, and these events are very important for any organism. Even your muscle movements can be attributed to cell-signaling events like these, so they happen faster than we can notice!
A Wiggly World
Throughout the last couple of decades, scientists that specialize in cell-signaling have been gathering information to support a more nuanced and complicated reality based on a simple concept; the protein “locks” are constantly wiggling and making tiny movements that help small molecules fit snuggly inside. The subtle but constant shifting of protein molecules means that that proteins take on different shapes or conformations very rapidly, but they spend more time in certain shapes that are more favorable. Without a key to keep the protein in an “unlocked” state, it’s more energetically favorable for that protein to stay locked.
Choppy Waters Ahead
Think of a lake with choppy waters—that’s an “energy landscape” for a protein.Dips and troughs are lower, preferable energy states, and peaks are brief high-points that can’t be sustained longer than a moment. What all this means for scientists studying protein micro-movements is that proteins spend most of their wiggly-time in conformations that are “locked”, but they briefly wiggle into “unlocked” and “partial unlocked” states too. This variety of states corresponds to the troughs and peaks in a choppy lake. These constant tiny movements, (or ‘wiggliness’ as I prefer) are a foundation to another concept important to drug development called biased agonism.
Biased Agonism – In Between Locked and Unlocked
The small molecules or drugs that act as keys are sometimes called agonists. There’s a bunch of different agonists for different protein locks, and some “fit” better than others, which cause them to change shape. But there’s also “kinda-unlocked” “mostly-unlocked” and “mostly-locked” shapes too, and potentially anything in between depending on which small molecule keys are being used. All these different keys still activate the protein signaling to a degree, but these partial activations are just as important to cell signaling as are the “fully unlocked” and “fully locked” states. In certain cases, different agonists can cause completely different cell signaling pathways by changing the lock’s shape in different ways. Scientists are learning to understand the nuances of cell signaling in order to develop better, more targeted medicines, as well as methods of delivering those medicines that are more relevant to complicated systems.
We’ve come a long way from not knowing how drugs affect us, but there are a lot of challenges ahead for pharmacological scientists investigating and developing better medicines. If you’re interested in learning more about drug discovery and the wiggly world of molecular medicine, check out videos like this.
About the author:
Jeremy Burton is a first-year PhD student in Pharmaceutical and Biomedical Sciences at UGA, studying GPCR-mediated angiogenic and inflammatory pathways in chronic lung diseases. Aside from frequently getting lost in his work and studies, he also enjoys getting lost in in his fantasy writing and worldbuilding, watching animated movies with his fiancée, or playing games with his friends online. He can usually be found at Pharmacy South where he works, or potentially anywhere else on campus googling how to get home on his phone.