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THE easiest way to find new
drugs may be to start with an old
one. So say researchers who have
transformed an antipsychotic drug
into a potential treatment for
prostate cancer. Their technique
could offer low-budget academic
labs and biotech start-ups a chance
to compete with big pharma.
One of the main goals of
prostate cancer research is to find
a drug that blocks the androgen
receptor, a hormone receptor that
plays a key role in the development
of the disease. Existing drugs are
unsatisfactory, so Ruben Abagyan,
a computational structural
biologist at the Scripps Research
Institute in La Jolla, California,
and his colleagues set out to find
a better one.
The standard approach to this
task would be to screen tens of
thousands of small molecules in
lab cultures looking for anti-
androgenic activity. Once a few
candidates are found, developers
would begin the expensive
process of testing how the
compounds behave in the body.
Most candidates fail, often
because they are not easily taken
up by the body or because they
prove to be toxic.
In the hope of speeding up the
process, Abagyan’s team began
with a database of the chemical
formulas of all approved drugs,
then used three-dimensional
molecular modelling software to
predict which would fit into the
critical region on the androgen
receptor. The best fits came from
three antipsychotic drugs called
phenothiazines.
In lab tests, two of the three
weakly blocked the androgen
receptor. The researchers then
tested 10 other molecules that
differed slightly from the
originals. One of these turned out
to have strong anti-androgen
activity and, as a bonus, it lacked
the antipsychotic effect of its
parent molecule (Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.0609752104 ).
Drug companies have now
expressed interest in testing this
and a related anti-androgenic
compound the group found later,
says Abagyan.
Phenothiazine antipsychotics
are known to have some
anti-androgenic side effects,
so in retrospect the new use is
not totally unexpected. However,
the researchers were not aware of
this at the time and chose the
drugs solely on their shape. They
say the strategy of looking for
potentially useful side effects
may actually be harder than
screening all drugs using
molecular modelling. “We’re
interested in molecular effects,
and the side effects are in terms of
symptoms,” says Abagyan. “The
connection isn’t simple.”
Abagyan’s approach may
indeed offer a useful short cut
to new drugs, says Michael
Sundstrom, who heads the
University of Oxford’s Structural
Genomics Consortium. However,
he cautions, just because an
existing drug has been approved
does not mean a related molecule
will be just as safe. “Experimental
testing needs always to follow,”
he says. “But to save resources,
and perhaps for smaller
laboratories that do not have the
resources for a major screening
effort, it is definitely an area that
will grow.” Bob Holmes ●
How to teach an old drug new tricks
“The team began with a database
of all approved drugs, then used
software to model the best one
to treat prostate cancer”
SOUNDBITES
‹ Scientific research must be encouraged and promoted, so long as it does not harm other human beings, whose dignity is inviolable from the very first stages of existence.›
Pope Benedict XVI endorses adult
stem cell research, distinguishing it
from that using embryonic stem cells,
which the Roman Catholic Church
condemns (AFP, 27 June)
‹ We can’t watch the neurons making connections, but we can watch a child’s smile disappear.›
Rebecca Landa, author of a report
in Archives of General Psychiatry
that suggests children as young as
14 months can develop autism
(USAtoday.com, 3 July)
‹ Contrary to popular belief, and their sharp teeth, piranhas are omnivores. They are scavengers more than predators.›
Anne Magurran of the University of
St Andrews, UK, presents research that
shows the fish have an undeserved
reputation (TimesOnline, 2 July)
‹ Most of us remain fair-weather environmentalists.›
Phil Downing of pollsters Ipsos
Mori, which found that many British
people remain unconvinced about
the severity of climate change (Press
Association, 3 July)
‹ We are at a crossroads like the start of the Renaissance, where you couldn’t just leave reading and writing to the kings and priests any more. Ordinary people have to keep up. In the world we live in you have to become scientifically literate or you will fall quickly from view.›
Natalie Angier, science editor of The New York Times, warns against a
perceived growing public scientific
illiteracy (The Observer, London, 1 July)
www.newscientist.com 7 July 2007 | NewScientist | 11
PHOT
ON
ICA
–Existing drugs can multi-task–
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