Medicinal chemists face a multitude of hurdles trying to discover new and effective therapeutics for the treatment of disease.
In the University of Arizona’s BIO5 Oro Valley facility is a team of College of Pharmacy researchers attempting to address these "speed bumps" along the path from bench to bedside by utilizing new automated technologies and fast chemical methods to increase the rate at which new hypotheses in drug discovery can be effectively evaluated.
"We have the personnel, process flow and infrastructure to work in a high-throughput modality producing libraries (i.e., collections) of potential drugs," said Christopher Hulme, professor in the department of pharmacology and toxicology at the College of Pharmacy and co-director of the BIO5 Oro Valley drug discovery facility.
Hulme compared this to a historical precedent in the auto industry: "People used to make cars one at a time. Henry Ford then invented the assembly line, enabling tremendous productivity gains in product output. That’s somewhat analogous to what we’re doing. Used at the right time, assembly line high-throughput approaches can be tremendously enabling."
Innovative efficiency in the drug discovery setting is an invaluable tool in helping scientists close in on disease treatments. When creating a new drug, scientists are often tasked with looking for small drug-like molecules that have the ability to bind to and modulate the function of misfiring target proteins, critical in the development of a disease or illness.
Through such modulation of this protein function, the drug hunter can disrupt messages that initiate disease progression that are being directed to the control center of the cell. For example, in cancer cells, messages transmitted through these protein networks may halt natural cell death mechanisms (apoptosis), resulting in overproduction of cells and tumor formation. Blocking proteins in such an aberrant pathway thus has the potential stop tumor growth.
However, the art of designing a molecule to bind tightly to a protein is not always simple. When a scientist develops a hypothesis for effective binding, it may take months of testing hundreds or even thousands of molecules to ultimately find one with sufficient activity.
Moreover, for a molecule to reach the organ or tissue where disease has emerged, it generally has to be sufficiently water soluble and metabolically stable enough to survive the rigors of passing through the liver. Side effects of potential drugs are also commonplace, leading to toxicity through interaction with proteins, which would be undesirable to modulate.
Thus, the selectivity for binding of the drug candidate to the aberrant protein is critical. These obstacles result in high failure rates for many drug candidates; enabling new chemical and computational technologies helps scientists advance their research by alleviating many of them.
Hulme’s lab is utilizing new automation to dispense reagents (chemicals or substances added to promote a chemical reaction) into multiple vessels all at one time. Using these technologies allows the scientist to walk away from the robot and perform other tasks while 50 reactions proceed to completion. Using these platforms, work that would normally take two days takes only five minutes.
"The gems we have here are the mass-triggered purification systems," Hulme said. "These systems can be loaded with 100 crude, impure potential drugs, and through automated chromatography, triggered by observation of the molecular weight of the drug, all 100 samples will be purified and returned to the drug hunter for testing in biological assays."
According to Hulme, the mass-triggered purification systems in the BIO5 Oro Valley analytical lab can produce the same number of compounds in a month that a scientist might produce during all of the work required for his or her doctorate.
But it doesn’t stop there. The compounds are then sent to a chemical library, where a large collection of molecules are safely held in stasis. These molecules can be distributed at any time and evaluated against any biochemical target a scientist wishes, enabling testing of thousands of molecules of different shapes and sizes to optimize protein binding. This collection is the largest set available in Arizona, with more than 100,000 molecules.
"This gives you more shots on goal and enables many scientists to test a multitude of hypotheses very, very quickly," Hulme said.
If scientists are still finding it difficult to unearth a molecule that can bind to their target protein, virtual screening can be employed using 3-D computer models of the protein to couple it with thousands (if not millions) of molecules from both commercially available and BIO5 Oro Valley libraries. The molecules deemed to bind with the highest affinity by the computer software are then purchased and evaluated in real time for affinity to the protein of interest.
"This has been a wonderful experience," said Alex Laetsch, research specialist and compound manager. "It's opened my eyes to the way pharmaceutical drug discovery works."
Hulme said his lab has also been putting together a selection of molecules for targets that have been classified as "undruggable," i.e., families of proteins that have not yet found small molecule modulators that have progressed into man. Indeed, when new families of proteins are discovered, there is often little information known about their relevance.
Hulme believes scientists frequently have taken a "rear-view mirror approach" to the discovery of new drugs for these emerging families of proteins. In the past, these protein families have simply been screened against molecules that have been extensively designed for other target families. There is now a consensus in the drug discovery community that the universe of molecular diversity has not been sufficiently explored, and these targets might well be "druggable."
"To address this, we have to jump to new areas of space, where no one has been before," said Hulme. "Not in six or seven steps, but in one or two steps, utilizing innovative, expeditious chemical technologies amenable to the construction of libraries of small molecules."