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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 PHOTONICA Existing drugs can multi-task

How to teach an old drug new tricks

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Page 1: How to teach an old drug new tricks

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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