Rational Drug Discovery

From Pfizer Pharmaceuticals

I don't normally blog from ads, but this is a good description of the rational drug discovery process.  I suggest you also look at the original link.

Original link:  https://www.getscience.com/What-it-Takes-to-Discover-and-Develop-a-Medicine#intro

DRUG DISCOVERY BEGINS with a team of scientists identifying a particular disease or condition that has an unmet medical need — either there is no treatment available or existing medicines can potentially be improved upon. Starting with a hypothesis about the cause of a disease or condition and thus a potential method of treatment, the journey to develop a new medicine can take up to 12-15 years and requires the passion, rigor and ingenuity of, on average, about 1,200 scientists, including clinicians, physicians, and other experts. “I like to think about drug discovery as solving a very complex jigsaw puzzle with many thousands of pieces,” says Mark Noe, Vice President of Discovery Sciences in Pfizer’s Groton, CT Research and Development site. “The team arranges the pieces in front of them, and they may start with a corner or with the edge pieces because you have some idea of where those pieces are supposed to go. And then you build the puzzle towards the middle as you progress. There are moments of exhilaration when you make an advance by finding some pieces that do fit together, but you often run into problems and need to rethink your approach in order to complete the puzzle.” Here’s the story of solving that puzzle, and of some of the people who work toward putting it together.

The drug discovery process begins with observing how a disease changes biological processes in the body, even if the exact cause of such changes isn't known. Researchers home in on what might be causing the disease, typically with the goal of identifying proteins in the body that might be involved in this disease process. They then form a hypothesis that inhibiting or activating a specific protein might potentially help to treat the disease. Proteins are the most common drug targets because they play so many critical roles in the body, performing a variety of biological processes, from mounting an immune response to facilitating nerve and hormone responses. A drug target can also target DNA or RNA. A good target is whose activity can be both linked to the way the disease works and also modified by a drug, be it a small molecules or a biologic such as an antibody.

Scientists use several methods to find a molecule that can serve as a potential starting point for creating a new medicine. Often this process begins with a compound "library," which is a collection of small molecules that some scientists might use to "screen" against a biological target to see which molecules can change the activity of the biological target. They may screen millions of these compounds for their ability to interact with the intended target. Of those screened, if they are lucky, the researchers will eventually identify one or more “lead” compounds that constitute a "hit," which will continue to be optimized through safety and efficacy testing. A variety of screening methods are used to identify lead compounds. Overall, the process of hit identification is very unpredictable, which makes it all the more momentous when researchers decide on a lead compound to advance to the next stages.

In contrast to the trial-and-error process of hit identification, rational drug design begins with knowledge of the shape of the protein target and uses computational techniques to "build" a molecule from scratch that optimally fits the receptors on that target. Computer-aided 3-D modeling is used to virtually screen and design these compounds. To do structure-based design, scientists need to understand the form and function of a molecule. They use high-tech tools, such as crystallography — X-ray studies of a crystallized protein — and electron microscopes, to determine the 3-D structure of a molecule and where on the target protein the compound could bind.

It works! Years of study, hundreds or thousands of tests, have led to a compound that shows signs of potentially stopping or reversing a disease. It's exciting, but there still remains a long road ahead: It's time to learn, through a series of carefully managed clinical trials, if the compound that has shown promising results in the lab can be a safe and efficacious treatment for real patients.