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DESIGNING DRUGS VIRTUALLY

P harmaceutical companies and medical researchers are constantly trying to find new
drugs that will provide better treatments for cancer and other serious illnesses. Until
recently, this process was largely a matter of trial and error.
Disease-fighting drugs typically work by attacking a disease-causing protein that is
harmfully interacting with other molecules in the body. The drug is able to stop these interactions
by connecting to the protein, and either restoring healthy interactions or compensating for the
unhealthy ones.
A drug connecting to a protein has been likened to a key fitting into a lock. In the traditional
drug discovery process, drug makers would be looking for the “keys” while ignoring the “locks.”
They sifted through natural substances found in soil, dyes and industrial chemicals, and failed
compounds from previous drug research efforts. They would test their samples for their impact
on diseased cells. Once in a great while, as in the case of penicillin, one worked, but for the over-
whelming majority of efforts, this was not the case.
Drug development companies tried to speed up the process by creating huge libraries of
potential compounds and using robots to quickly review hundreds of thousands of samples
to see if any worked. Machines would create thousands of chemicals per day by mixing and
matching common building blocks. Then robots would drop bits of each chemical into tiny
vials containing samples of a bodily substance involved in a disease, such as the protein that
triggers cholesterol production. A “hit” occurred when the substance and the chemical produced
a desired reaction. Way too much depended on chance. When researchers did come upon a new
treatment that worked, they often had no idea for many years why. They did not understand the
“key” or the “lock.” Very few effective medications were discovered this way.
Joshua Boger, a former Merck & Company scientist, decided to try a different approach called
structure-based design. In 1989, he formed a company called Vertex Pharmaceuticals, which
would focus on figuring out what a “lock” looked like so it could fashion the right disease-fighting
“key.”
It would not be easy to determine the shape of a “lock.” Proteins escape when X-rays try to
capture their images, so scientists must first crystallize the proteins and try to deduce their
shape by examining the patterns left by the X-rays deflecting around them. This work requires
powerful computers analyzing thousands of interference patterns.
Next, researchers must find a custom molecule to fit that particular “lock.” The molecule must
be able to bind to the target, be
synthesized and manufactured
in large quantities, and be
metabolized by the body at just
the right rate. Powerful com-
puters help evaluate the struc-
tures and properties of mol-
ecules that are most likely to
bind to that target and rapidly
search large database libraries
of chemical structures in order
to identify the most promising
candidates.
The discovery of the drug
called Xalkori, a treatment for
a rare and resistant form of lung
cancer, is one example of how © style-photography.de / Shutterstock

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