Emory Report
July 18, 2005
Volume 57, Number 35


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July 18, 2005
$9M NIH grant helps establish national molecular library

BY holly korschun

The National Institutes of Health (NIH) recently announced it is awarding nearly $9 million to Emory as part of a nationwide research network of nine centers that will use high-tech screening methods to identify small molecules that can be used as research tools.

By screening promising molecular targets against thousands of small molecule compounds, the Molecular Libraries Screening Centers (MLSCs) will give scientists more information about key biological processes involved in human health and disease. Raymond Dingledine, professor and chair of pharmacology in the School of Medicine (SOM), is principal investigator for Emory’s MLSC.

The screening centers will use high-throughput robotics equipment to screen huge libraries of small molecule compounds against cells or proteins already identified by laboratory scientists as playing key roles in disease processes. The screening process will single out compounds that modify the target proteins. Eventually this process may help the scientists identify promising new targets for diagnosis, treatment and prevention.

The national screening program is part of the “New Pathways to Discovery” initiative within the NIH Roadmap for medical research. The network is funded by all of the institutes of the NIH and co-administered by the National Institute of Mental Health (NIMH) and the National Human Genome Research Institute (NHGRI).

Emory’s MLSC builds on the University’s recently established Emory Chemistry-Biology Center for Drug Discovery under Dingledine’s leadership, which is co-directed by the SOM’s Haian Fu, professor of pharmacology, and Dennis Liotta, professor of chemistry in Emory College. The drug discovery center is an interdisciplinary collaboration among research departments in the SOM and the college to screen promising protein targets identified by Emory scientists. Fu and Liotta, along with James Snyder, professor of chemistry in the college, also are co-principal investigators of the new NIH molecular screening center.

The national molecular libraries screening program will eventually enable researchers to explore the hundreds of thousands of proteins believed to be encoded by the approximately 25,000 genes in the human genome. At present, only about 530 proteins, out of more than 30,000 proteins identified by the human genome project, have been identified as targets of marketed drugs.

“Now that all those proteins are known, we need to identify more small molecules that can alter the function of those potential targets,” Dingledine said. The molecular libraries screening program is an effort by NIH to take an efficient, high-throughput approach toward the discovery of many more useful compounds.

Dingledine said Emory’s success in gaining the national drug screening center designation owes a great deal to the Georgia Research Alliance (GRA), which contributed nearly $500,000 for the purchase of high throughput screening equipment for the drug discovery center, which owns a library of 100,000 small molecule compounds.

“The strength of our chemistry department and the deep interest of our chemists in drug development is a key differentiating factor for Emory as a drug discovery center,” Dingledine said.

“Until very recently, this kind of early drug discovery technology was available only to large pharmaceutical companies that could afford the very expensive equipment and huge libraries of compounds required to identify small molecule compounds that could alter the function of molecular targets,” Dingledine continued.“ Several factors combined to allow academic institutions to begin participating in this discovery process, including the sequencing of the human genome, more affordable equipment, and the availability of compound libraries for purchase from small biotechnology companies.”

Two kinds of robotics equipment in Emory’s drug discovery center will combine to give Emory scientists the most precise screening capabilities available. A robotic liquid handler is a highly automated pipette system that picks up minute amounts of liquid containing compounds of interest and combines them in tiny wells with potential protein targets. Another robotics machine uses an autofocusing microscope that images each combination of protein with its molecular target. The cells are marked with fluorescent dyes. The massive amounts of information gathered from the liquid and imaged screening are analyzed using bioinformatics technology capable of sorting through millions of bits of data to identify the most promising combinations.

In the past, this kind of analysis was a painstaking process accomplished by a technician pipetting liquids for each compound individually from one test tube to another, then writing the results by hand in
a notebook.

The academic drug screening centers will not be competing with large pharmaceutical companies, Dingledine said, because academic centers will be working to identify drug targets that currently are not being pursued, but that have potential therapeutic value.

“Academic biomedical laboratories have a Zen-like focus on the properties of disease-related proteins,” he said. “We tend to put a lot more effort into understanding the detailed working of proteins than do pharmaceutical companies. And in addition to giving us drug discovery capability, this new center provides a powerful new tool for our investigators to address important questions related to disease.”

In addition to Emory, the eight other institutions receiving grants as part of the Molecular Libraries Screening Centers Network are the universities of New Mexico, Pennsylvania and Pittsburgh; Vanderbilt University; Columbia University Health Sciences; the Southern Research Institute in Birmingham, Ala.; The Burnham Institute, La Jolla, Calif.; and The Scripps Research Institute, La Jolla.