libraries through chemistry
CAS chemistry gets $10.7 million to develop molecular library
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.
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
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
“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
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.”