Drug molecules interact with their targets, such as proteins or
enzymes, by attaching to them in a way that neutralizes the target's
undesirable effects in the body. This is sometimes called the
"lock-and-key" method. The new approach offers scientists far greater
control over the three-dimensional structure of a key class of molecular
compounds, making it easier to fashion drug molecules that fit their
targets in the right way.
"Now we've got a lot more control over the shape and orientation of
this class of drug compounds, and this essentially gives us greater
flexibility in creating effective drugs," said Jonathan Ellman, the Yale
chemist who led the experiment.
The research reported in Science revolves around piperidines,
a class of organic compounds widely used in pharmaceuticals, including
the familiar drugs quinine, morphine, oxycodone, Plavix, Cialis, and
Aricept. Piperidines are core structures, or scaffolds, upon which
molecular fragments — parts of the drug molecule — can be displayed for
binding to a drug's targets. The scientists have shown a way to generate
different piperidine derivatives by varying acid strength.
"Our research allows us to make new piperidines easily," Ellman
said. "The approach has biomedical relevance because the scaffold upon
which the fragments are displayed is present in many of the most
The research is being published without patent constraints and could
be used by drug developers immediately, said Ellman, who is the Eugene
Higgins Professor of Chemistry and professor of pharmacology. "I believe
that this is the most effective approach for rapidly translating this
work into new drugs," he said.
The paper is titled "Proton Donor Acidity Controls Selectivity in
Nonaromatic Nitrogen Heterocycle Synthesis." Other authors are Simon
Duttwyler, Shuming Chen, Michael K. Takase, Kenneth B. Wiberg, and
Robert G. Bergman.
The National Institutes of Health, the U.S. Department of Energy, and the Swiss National Science Foundation provided support for this research.