While many proteins have a single active site, there are many allosteric binding sites available for discovery and utilization. Due to conformational differences among proteins, allosteric binding sites will be unique to each protein creating a solution to the specificity problem. Allostery also offers a degree of control that is unattainable with targeting the active site, allowing scientists to fine-tune how a drug will alter the activity level of a given protein. Our bodies already use allostery to tweak activity levels to maintain cellular homeostasis, so it makes sense for drug development to be moving in this direction. Importantly, allosteric drugs will not compete with natural ligands which prevents unwanted downstream consequences.
Allosteric drugs were usually stumbled upon or first identified by high-throughput screening meaning thousands, or even millions, of different candidate molecules were tested on a given protein to analyze the resulting effect on activity. Now, it is much more likely that scientists are looking at the entire protein conformation and searching for allosteric binding sites unique to proteins. This process is then followed by looking for small molecules that fit the chemical makeup of allosteric pockets. Once identified, a molecule can be tested. Allosteric modulation occurs when a drug binds a protein in an identified allosteric site. Upon binding, an allosteric drug can alter the likelihood that the agonist will bind the active site, augment or lessen an agonist’s effects, or induce a conformational shift to turn the protein on or off in the absence of an agonist. In some areas of medicine, like an oncology, a drug may even stabilize the non-native form of a protein or protein complex or target the protein for degradation as a treatment option.