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Target Identification and Validation
For the past twenty years, basic scientists at Georgetown University have been studying the proteins that cause disease. Often mutated, or behaving unusually within the context of a cell, these specific proteins identified by scientists are the most basic cause of any disease, ranging from cancer to Alzheimer’s.
The decades of work that go into identifying the key proteins causing a disease are the groundwork for drug discovery. These proteins are potential targets for new drugs to act on. Basic scientists have discovered these targets, and validated them through repeated experiments (including knock out models, siRNA, and mechanistic studies), to ensure that a target protein that enters into the drug discovery phase of the research pipeline is genuinely responsible for the disease condition.
The true process of drug discovery begins after the validation has been completed. Medicinal chemists like Dr. Brown, who understand the nature of molecules from the perspective of chemistry and also understand the role of different molecules in the human body, develop small molecules that stop the target protein from causing the disease.
There are a few important characteristics that a molecule must have to be considered for drug development:
- It must be selective in the way it interacts with proteins to ensure that it only acts on the disease protein,
- It cannot be toxic,
- It must be distributed in the body in a way that ensures it reaches the disease site, it needs to be easily manufactured, and
- It needs to be something that no-one has discovered – or more importantly, patented – before.
Drug discovery experts use three different approaches to find a small molecule that will serve as an effective drug: physical screening, virtual screening, and by protein structure based design.
To physically screen small molecules against a disease target protein, chemists use known databases of small molecules that have already been identified and are often patented. In plates that have 96 wells, the target protein is loaded into each well in microscale amounts and a different small molecule is added to each one. When the chemist finds one that reacts, often seen through a change in the color of the liquid in the well, he or she can then modify it into a new molecule that has a more potent effect on the target.
By knowing the molecular structure of the target protein, which often takes years of work by basic scientists, chemists can compare the structure of the protein to models of the structure of small molecules. This allows the scientists to rapidly and cost-effectively screen the target against a potentially infinite library of molecules. Once several potential matches have been found using the modeling software, the small molecules will be physically tested for their potential to react with the target protein.
Chemists can also specifically design small molecules to fit into the known physical properties of the target protein. Using software that can identify the important properties that need to be matched – such as volume, charge, steric constraints, and hydrogen-bonding ability – chemists can discover the precise reciprocal properties needed in the drug molecule. After that, it is a matter of creating this molecule with the same techniques that students learn in organic chemistry labs.
Once several likely candidates have been identified through one of these processes, medicinal chemists not only perform studies to ensure that the protein and drug interact correctly in a test tube, but also in tissue cultures. This is important because the drug must act within the context of a cell, which is a much more complicated environment than a sterile test tube in a lab.
The next stage in the Research Pipeline carries the small molecule from the drug discovery identification stage and prepares it as a drug, ensuring the molecule interacts is also effective within the infinitely more complex environment of the body. Using preclinical models, scientists study whether the potential new drug arrives at the target cells in the appropriate tissue, reaches this target before it is removed from the body (through the urine or by metabolism), and does act to stop the disease process. One of the other important considerations is the toxicity of the drug to other tissues. Before a trial can begin in the clinic, scientists must prove that the new drug is safe.
Phase 0 trials study the distribution of the drug in the human body. Using non-therapeutic doses that are tagged with radiolabels, doctors will be able to view where the drug is delivered within the body using applications such as PET imaging. This will enhance the Phase 1 process because physicians will already know where in the body the drug is acting.
Phase 1 trials establish the safety of the drug for humans. Before these trials can take place, investigators must submit an Investigational New Drug application to the Food and Drug Administration to receive permission to run the trial. Looking at potential short-term toxicities, patients in Phase 1 trials are the first to receive therapeutic doses of the drug. In cancer clinical care, these trials often offer patients the only treatment option for advanced disease.
Phase 2 and 3 trials focus on the effectiveness of the drug. Typically, these are large trials conducted in partnership with industry. Phase 2 trials are specific to identifying the appropriate dose for patients, while Phase 3 examines the drug’s efficacy in treating the disease and it’s short-term effects on the patient. Industry most often joins the drug discovery and development process at the Phase 2 stage when synthesis of the drug needs to be scaled up to provide enough of the molecule for the trials.
After the completion of Phase 3 trials, information about all of the trials is submitted to the Food and Drug Administration for approval. (contributions by Allison Whitney)