NSF PR 97-31 - April 30, 1997
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Study of "Mirror Image" Molecule Supports
New Approach for Drug Design
Scientists have recognized for more than a century
that some molecules exist as pairs of mirror images.
But, are such molecules really "righties" or "lefties",
chemically speaking? New research funded by the National
Science Foundation is providing an answer.
Recognizing whether a molecule's right-handed or left-handed
form binds more tightly to another molecule can be
critical for the design of new drugs, since one form
might prove beneficial while the other could be ineffective
or worse -- harmful. For example, when pregnant women
in the 1950s were given a 50/50 mixture of right-handed
and left-handed versions of a drug called thalidomide,
only one form was effective, while the other resulted
in profound birth defects.
Since then, methods have been developed by drug companies
to selectively synthesize or separate left-handed
and right-handed molecules. However, those methods
are not always cost-effective or efficient and do
not allow chemists to tell beforehand which version
might offer the best candidate for a future drug.
Now, an international team led by Andrew McCammon
at the University of California, San Diego has used
a form of computational wizardry to study a famous
mirror-image molecule called bromochlorofluoromethane
(CHFClBr) -- a chemical used in every introductory
chemistry course to illustrate "handedness" in molecules.
The procedure, described in the current issue of the
Journal of the American Chemical Society,
could also be used to help chemists predict which
mirror-image molecule might be worthwhile pursuing
for drug development.
"This work is a wonderful illustration of the power
that simulation and theoretical approaches, when combined
with experimental approaches, can bring to solving
a basic scientific question," says Kamal Shukla, program
director of molecular biophysics at NSF.
It was French chemist Louis Pasteur who discovered
mirror-image molecules in 1848, when he showed that
a compound obtained from wine -- tartaric acid --
formed right-handed and left-handed crystals. Pasteur
was able to visually identify the two different forms,
and painstakingly separate them with tweezers.
The most common examples of compounds whose molecules
exist in two different mirror-image forms consist
of, or include, a single carbon atom bound to four
different groups. That's true for simple organic molecules
and for amino acids that make up key biological proteins
and enzymes, which become targets for drugs. A particular
biological receptor for a drug can be likened to a
glove in that a left-handed drug will fit on a left-handed
receptor. A right-handed drug will fit less well,
if at all, into a left-handed receptor and could cause
serious side effects, as was the case with thalidomide.
To find a solution to this problem, the UCSD-led researchers
called upon computational techniques that permit subtle
changes to be made in the shape or location of carefully
chosen atoms, ultimately altering the binding strength
of molecules to their targets. In drug development,
such knowledge is important, since the tighter the
binding, the more effective a drug is likely to be.
Since the method conjured up medieval images of replacing
atoms of lead with atoms of gold, it was dubbed "computational
alchemy" by its originator, Andrew McCammon. Computational
resources of the San Diego Partnership for Advanced
Computational Infrastructure were used in the research.
Editors: Photos of the "leftie" and "rightie"
molecules, as well as a cartoon illustration of how
they work, are available by contacting Cheryl Dybas
at (703) 306-1070.
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