It doesn’t matter if you ask a pharmaceutical
company executive, an overbooked doctor or a patient seeking
treatment, when it comes to discovering new drugs to treat illness,
everyone agrees. We need better drugs faster.
The drug discovery process, however, is notoriously time-consuming
and expensive, requiring scientists to synthesize and test tens
to hundreds of thousands—sometimes millions—of compounds
in the hopes of finding one that will interact with the body
in the desired way.
Now, advances in computer-assisted drug discovery (CADD) are
improving the way scientists do their work. Robert Pearlman,
Coulter R. Sublett Regents Chair in Pharmacy in the College
of Pharmacy at The University of Texas at Austin, is a pioneer
in the field.
Pearlman’s CADD software is used at almost every pharmaceutical
company on the planet. One of his first programs, Concord™,
has been distributed commercially since 1986, and new products
continue to issue from his newly established software company
Optive Research Inc. Each software product serves a different
purpose, but they are all designed to help scientists make better
decisions about which compounds to synthesize and test.
“Understanding how molecules interact with one another
is the key to drug discovery,” Pearlman explains. “Drug
discovery boils down to finding a small molecule—the drug—that
interacts in an optimal fashion with a large biomolecular ‘target’ or ‘receptor,’ often
a protein. What makes drug discovery so difficult is that there
are a near-infinite number of small molecules that could be
synthesized and tested as potential ligands for each target.”
CADD methods assist scientists by enabling computer-based predictions
of how well a small molecule might interact with a given biomolecular
target even before that small molecule has been synthesized.
By synthesizing and testing only those compounds that are predicted
to be active, scientists can greatly reduce the number of small
molecules they actually synthesize and test.
Discovering a new drug requires taking a biological target,
or receptor, and discovering a compound that will fit that target
and thus alter the body’s chemical state.
Before computer-based methods were developed, scientists basically
proceeded by trial and error. On average, a pharmaceutical company
would synthesize 8,000 to 12,000 compounds in a single discovery
effort. This could take years.
In the meantime, pharmaceutical companies were amassing samples
of compounds they had synthesized and tested. In the mid 1980s,
a large pharmaceutical company might have had a database of
half a million compounds, represented as the familiar two-dimensional
chemical structures we see in chemistry textbooks.
“People dreamed of performing calculations on three-dimensional
structures to identify those which would fit into a particular
receptor,” Pearlman says. “But as late as the mid-80s,
it would take anywhere from several minutes to half an hour
to generate the 3D structure of just one drug-sized molecule.
Faced with the daunting task of converting databases of hundreds
of thousands of compounds, pharmaceutical companies never seriously
considered large-scale conversion to 3D.”
Pearlman’s first commercially distributed CADD software,
Concord™, changed all that. It was the first program in
the world to rapidly and automatically convert two-dimensional
chemical representations into three-dimensional chemical structures.
The current version of the program can convert half a million
drug-sized compounds into 3D structures in less than an hour.
Nearly two decades after its creation, it remains the industry-standard
tool for this critically important process.
Concord™ enabled new strategies for computer-assisted
drug discovery, the first of which was 3D-searching. After generating
3D structures of compounds in a database, 3D-searching software
enables scientists to quickly search through that database looking
for compounds with the right size and shape for optimal interaction
with the 3D structure of a particular target. Purchasing and
testing only compounds that are most likely to interact with
the target saves time and money.
Pearlman and his team soon started thinking about how they
could use the computer to generate structures of compounds that
had not yet been synthesized. A number of programs followed,
including a large, multi-purpose package called DiverseSolutions™.
DiverseSolutions™ software helps scientists choose which
compounds to synthesize from a subset of possible compounds
by assigning descriptors to specific elements of chemical structures.
From the beginning, Pearlman’s goal in creating the software
has been the same as that of the university: to make sure it
is used.
“First and foremost, we want to see the results of the
university’s research being used by the people it can
really benefit,” says Neil Iscoe, who directs the university’s
Office of Technology Commercialization. “Our overall goal
is the distribution of technology, and the vehicle for that
is commercialization.”
Since the mid-80s, Pearlman’s software has been distributed
on behalf of the university by the St. Louis company Tripos
Inc. Tripos pays royalties back to the university and to Pearlman’s
lab.
Over time, the lab grew and started morphing into a software
company of its own.
“Once you’ve got commercial software of commercial
interest and you’ve got a commercial user base, you’ve
got commercial expectations regarding quality and user interface
issues,” Pearlman says.
The obvious solution was to spin out a software company that
could be self-sustaining outside of the university and Optive
Research was created in July 2003.
The five programs originally licensed to Tripos are now licensed
to Optive but continue to be distributed by Tripos and to generate
royalties to the university. The investment dollars paid by
pharmaceutical industry into research at the university are
returned many times over by successful commercialization.
Optive will at the same time develop new software and maintain
its relationships with industry partners. Pharmaceutical companies
will get the software that makes their job easier. Even the
Austin community benefits.
“Most of the time drug development goes to the east or
the west coast,” Iscoe says. “Optive is an example
of a company that sells technology both nationally and internationally
and does it from Austin. This can really help our community.”
It’s rare to find a situation in which everyone wins,
but this is one. And perhaps the ultimate winner is the patient,
the consumer, the individual hoping for relief from a malady
or even a cure for a disease.
“Optive Research is not about software distribution.
It’s about scientific research into improved CADD methods.
We are excited about the impact our software has had and will
continue to have on the drug discovery process, and we are gratified
by the notion that these benefits to society are rooted in the ‘technology
incubator’ which is The University of Texas at Austin.”
