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Better libraries through chemistry
CAS chemistry gets $10.7 million to develop molecular library

By Tim Stoddard

In the race to churn out new blockbuster drugs, pharmaceutical companies are hitting a wall in the development process. The chemical libraries they use to synthesize complex drugs are fundamentally limited, says John Porco, a CAS assistant professor of chemistry and pharmacology, and the poor selection is stifling innovation. For Porco and other organic chemists outside of industry, there’s an additional concern: the comprehensive libraries held by big pharmaceutical companies are the best collections out there, and they’re not freely accessible to academia.

Scott Schaus (from left), James Panek, John Porco (seated), Thomas Gilmore, and John Snyder will develop a new kind of chemical library at the Center for Chemical Methodology and Library Development. Photo by Fred Sway

In an effort to revitalize chemical libraries in the public domain, the National Institute of General Medical Science (NIGMS), part of the National Institutes of Health, has awarded a $10.7 million grant to a team of Boston University chemists to create the Center for Chemical Methodology and Library Development (CMLD). It is the largest grant ever received by the chemistry department, and “it will put Boston University at the forefront of one of the most exciting frontiers of synthetic organic chemistry,” says Tom Tullius, a CAS chemistry professor and chairman of the department. Directed by Porco, the center will pioneer new methods for synthesizing and purifying a more diverse library of molecules.

A chemical library doesn’t look very much like Mugar or other paper-based repositories of literature. It consists of thousands of small liquid samples of molecules contained in compact square containers. At CMLD, researchers will use new techniques to synthesize molecules that are not available in existing libraries. Like a jukebox selecting a song, a robot can retrieve a desired molecule from the library and provide information on its structure and on how it was prepared. In addition, researchers will be able to borrow samples from the library and use them in their own laboratories.

Over the next three years, CMLD will replace the chemistry department’s existing fourth floor laboratories at 590 Commonwealth Ave., but when a new CAS Life Sciences and Engineering building is erected, the center will relocate there.

Along with Porco, CMLD’s three principal investigators are James Panek and John Snyder, both CAS professors of chemistry, and Scott Schaus, a CAS assistant professor of chemistry. All four have trained in organic chemical synthesis, but each brings a different subspecialty to the CMLD. “We approach problems from different directions,” says Schaus, “and only by taking advantage of that were we able to assemble a cohesive grant proposal.”

That diversity of expertise was one of the factors that impressed NIGMS. “We are very excited by the obvious synergy among the investigators as well as the very thoughtful and complete plans that they presented for their core facility and for outreach to the research communities,” says John Schwaub, the NIGMS chemist who spearheaded the CMLD initiative.

The problem with existing chemical libraries, says Porco, is that they all come from the same stock of basic chemicals. Larger manufacturers such as Pfizer and Glaxo-Smithkline, as well as academic institutions such as Boston University, all buy their simple stock chemicals, the building blocks for bigger molecules, from the same suppliers. That lack of diversity in building materials is already limiting the range of products that chemists can ultimately build, Snyder says. “There’s a key need to make new kinds of building blocks for this library,” adds Porco.

The primary goal of CMLD is to build a better library, but ultimately the molecules housed there will be useful in medicine and in answering basic questions in biology. “We’re not trying to set up a small pharmaceutical company here at BU,” says Schaus. “We’re actually interested in making compounds that you can use to study biological functions.”

Researchers from Harvard Medical School, Yale, and BU’s biology department are already clamoring to access the center’s forthcoming library, says Thomas Gilmore, a CAS professor of biology. Gilmore will be the director of the CMLD’s Chemical Library Consortium, an affiliation of chemists and biologists in the Boston area who will collaborate on research projects tied to the new library. “The consortium was organized at the NIH’s request for the CMLD to have a component of outreach for the biological community,” Porco says. In addition, the library’s data collection will eventually be freely accessible on the Web (www.bu.edu/cmld).

New molecules designed at CMLD could have potential pharmaceutical applications, says Gilmore. Diseases arise when proteins misbehave, but molecules made in the lab can stick to wayward proteins and enhance their function or disable them entirely. For Gilmore, who studies a faulty protein involved in various leukemias, the center could yield a useful compound for treating cancer.

“The applications aren’t limited to obvious medical purposes, like refining a drug,” he adds. “The library can help a lot of people who are doing basic research in biology.” For researchers studying biological processes -- the unfurling of a leaf, say, or the regenerating limb of a salamander -- the library could provide new tools for understanding the nature and function of proteins that are key to these processes.

CMLD will incorporate teaching into its research agenda. There will be numerous opportunities for undergraduate and graduate students to work with faculty in developing and applying the chemicals in the library. “The chemistry department already has a very vigorous undergraduate research component,” Panek says, “and we intend to emulate that with the new center.”

11 October 2002
Boston University
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