High-Tech Robots’ Efforts Bear Fruit Thanks to NIH Roadmap

October 8, 2009 • Science Update

Researchers recently announced discovery of a new class of molecules that holds promise for blocking the clumps of protein that clog the brain in Alzheimer's disease . The new findings are the latest made possible by the NIH Roadmap Molecular Libraries initiative, which employs high-tech robots and molecular genetics to speedily screen molecules for their biological effects. The discovery required testing nearly 300,000 compounds — a task thought insurmountable just a decade ago.

"If you had to do that task by hand, it would take a person eight hours a day, five days a week, for 12 years to do what we can now do in three days," explained Dr. Chris Austin, director of the NIH Chemical Genomics Center (NCGC).

In its largest such search to date, the NCGC provided the small molecules screened for potential inhibitors of tau protein clumping in Alzheimer's disease. NCGC is one of a network of nine centers  funded at $70 million annually under the Roadmap initiative, now in its second phase. NIMH and NHGRI co-administer the program on behalf of NIH.

"Several new tools for biological exploration - including some that hold potential for new therapies - have recently entered the pipeline" said NIMH's Dr. Linda Brady, director of NIMH's Division of Neuroscience and Basic Behavioral Science and co-lead, along with Carson Loomis of NHGRI, of the Molecular Libraries Program. "Chemical vendors have even started selling some of the NIH-generated probes."

At its labs in Rockville, MD, NCGC robots work day and night performing automated high throughput screening. This technique borrowed from industry can rapidly screen vast libraries of chemicals, genes or drugs for their effects on cells and proteins. The Center transforms the findings into probes for use by NIH-funded scientists in search of better treatments for disease.

"Such small molecule probes can precisely tweak a cell's inner workings, providing a potentially powerful strategy for understanding biological pathways," explained Brady.

In the Alzheimer's study, University of Pennsylvania researchers used Genomic Center probes to pinpoint a class of chemicals called ATPZs that block the tau protein clumping. The researchers are following up with studies of ATPZs in transgenic mice, in hopes of paving the way for a new class of drugs to treat the disorder.

At the Vanderbilt University Specialized Chemistry Center for Accelerated Probe Development, Roadmap grantee Dr. Craig Lindsley's team has identified compounds that suggest a strategy for treating the thinking deficits in schizophrenia and Alzheimer's disease. The Vanderbilt researchers used high-throughput screening to pinpoint two compounds that selectively tweak a subtype of receptor, called M1, for the brain messenger chemical acetylcholine, which is known to be critical for learning and memory. These agents, which show few side effects, reversed thinking deficits in a rodent model of learning and memory.

Similarly, at California's Scripps Research Institute's Comprehensive Center for Chemical Probe Discovery and Optimization, another Roadmap funded Center, Dr. Hugh Rosen and colleagues have discovered selective probes for the brain's neuropeptide Y system. These hold potential for future development of anti-anxiety agents and perhaps for the treatment of alcohol abuse.

The Scripps researchers have also developed high throughput technology for quickly screening tens of thousands of compounds and unraveling the workings of still uncharacterized enzymes — previously labor-intensive tasks. Using this technology, they recently discovered compounds that can block certain cancer-related enzymes.

Another Roadmap grantee, Dr. Larry Sklar and colleagues at the University of New Mexico's Center for Molecular Discovery developed a high throughput way to simultaneously sort out complex cell mixtures and molecular interactions. Using this, they recently discovered a new compound, called G15, that regulates cell responses to estrogen. The research is advancing understanding of estrogen's role in breast, uterine, endometrial and ovarian cancers.

Moreover, G15 selectively turns off a key estrogen receptor also discovered by New Mexico scientists, suggesting a strategy for decreasing mortality rates associated with the cancers. The findings may also find applications in other estrogen-related disorders, such as immune system disorders and multiple sclerosis.

The new discovery was the latest in a line of studies by Sklar and collaborating New Mexico investigators that included identification of a compound, called G1, which, in contrast to G15, turns on the receptor. With such detailed understanding, it might be possible to someday selectively maximize estrogen's beneficial effects while minimizing its downside, say the researchers.

The information gleaned about small molecules is publically accessible on NLM's PubChem  website, another component of the Roadmap initiative.

"The website is used by 50,000 people daily," said Dr. Stephen Bryant, who directs the project. "It currently represents over 25 million unique chemical structures, with data on more than 700,000 compounds, the large majority from the Molecular Libraries Program."

References

Bachovchin DA, Brown SJ, Rosen H, Cravatt BF. Identification of selective inhibitors of uncharacterized enzymes by high-throughput screening with fluorescent activity-based probes . Nature Biotechnology. 2009 Apr; 27(4): 387-394. PMID: 19329999

Crowe A, Huang W, Ballatore C, Johnson RL, Hogan AM, Huang R, Wichterman J, McCoy J, Huryn D, Auld DS, Smith AB 3rd, Inglese J, Trojanowski JQ, Austin CP, Brunden KR, Lee VM. Identification of aminothienopyridazine inhibitors of tau assembly by quantitative high-throughput screening . Biochemistry. 2009 Aug 18;48(32):7732-45. PMID: 19580328

Dennis MK, Burai R, Ramesh C, Petrie WK, Alcon SN, Nayak TK, Bologa CG, Leitao A, Brailoiu E, Deliu E, Dun NJ, Sklar LA, Hathaway HJ, Arterburn JB, Oprea TI, Prossnitz ER. In vivo effects of a GPR30 antagonist . Nature Chemical Biology. 2009 Jun 5(6): 421-427. PMID: 19430488

Lebois EP, Bridges TM, L. Lewis M, Dawson ES, Kane AS, Jones CK, Xiang Z, Jadhav SB, Yin H, Kennedy JP, Meiler J, Niswender CM, Conn JP, Weaver CD, Lindsley CW. Discovery and characterization of novel subtype-selective allosteric agonists for the investigation of M1 receptor function in the central nervous system. ACS Chemical Neuroscience 2009.