Drug Design: Matching a Drug to Its Target

When we think of medicines, we often picture colorful capsules, pills, or liquids that cure illnesses or help us feel better. But how do these medicines go to the right places and how do they treat specific problems (or conditions) in our bodies? The answer lies in understanding how medicines are designed to have specific targets in our bodies.

In most cases, these targets are proteins, but the sequencing and assembling of the human genome has expanded how we identify drug targets. For example, mRNAs have become highly sought-after targets using siRNAs as therapeutic drugs. Here we focus on target proteins. These targets are chosen by investigators because they hypothesize that switching these proteins on or off will have a beneficial effect on a disease or condition. Because the shape of a protein determines its function, certain medicines are designed to fit into the target proteins in our bodies perfectly, thereby activating or inactivating them.

Ideally, a drug should only bind to the target associated with the condition it is meant to treat. This allows the drug to treat that condition effectively with minimal side effects. However, if a drug binds to other targets unrelated to the condition, it can cause unwanted side effects. Therefore, the goal is to create a drug that only fits into the target(s) associated with the condition.

To understand how drug-to-protein binding works, let’s look at selective serotonin reuptake inhibitors (SSRIs), which are commonly used to treat depression. Researchers discovered that people with depression have lower levels of certain neurotransmitters in their brains, including serotonin. Instead of providing more serotonin directly, scientists developed medications that keep the serotonin from being removed. These medications, SSRIs, attach to specific proteins called serotonin transporters, which are responsible for removing serotonin from the synaptic gap between neurons. By temporarily inhibiting the removal of serotonin, SSRIs increase serotonin activity in the brain, which can help relieve the symptoms of depression.

Developing the right molecular shape for an SSRI drug was challenging. Many early variants of SSRIs would bind to a variety of different proteins in the brain, causing unwanted side effects. However, through extensive research and testing, scientists eventually created SSRIs that are more likely to bind to serotonin transporters than other receptors. These new SSRIs were successful in treating depression with minimal side effects. Since then, several variations of SSRIs have been developed, further improving their effectiveness and reducing side effects.

Ongoing research continues to develop new SSRIs with even better results. Modern SSRIs have fewer side effects compared to older drugs, thanks to our increased understanding of proteins and how their shapes affect their functions. This knowledge has allowed for more precise and targeted drug development.