Making More Drugs...continued

What chemical is that?

If you make your chemicals in mixtures you save time, but you are left with a problem. What chemical is on what bead?

The simplest way to find out is to look, directly, with tools that detect the exact molecular weight (using a mass spectrometer) or the electronic environment of particular atoms (using a nuclear magnetic resonance (NMR) machine). There is just enough of a chemical on a standard bead for identification using these methods. Some methods work with the chemical attached to the bead; for others the ‘linker’ that holds the chemical to the bead must be sheared with light or acid or base.

If a library has been made for one specific purpose this approach can work. "The beauty of combinatorial chemistry is that you don’t really care about identifying everything, you just have to identify the active chemicals," says Ron Zuckermann, director of bioorganic chemistry at Chiron. Having determined the make-up of the few chemicals that turn off his protein of interest, Zuckermann will happily re-make these chemicals in bulk for further study.

But if you have a large library that will be used in many different projects, you may want to know what the chemical on every single bead looks like, and doing 100,000 NMR runs will take far too much time and money. This is where tags come in.

The first tags were peptides and oligonucleotides. Each time you added a certain nucleotide building block, say adenine, you could add a particular amino acid, say leucine. To identify the final oligonucleotide, the peptide is chewn off, one amino acid at a time. The order of amino acids gives the order of nucleotides, leaving the oligonucleotide intact for testing as a drug.

Once the chemistries got more complicated, the tags got more sophisticated. Affymax and Pharmacopeia, Inc. (Princeton, New Jersey) made tags that were more resistant to degradation by harsh chemicals, and more easily detected. But the complexity award goes to IRORI (La Jolla, Calif.), who embedded tiny radio-transponders in containers reminiscent of Houghten’s tea bags. A computer assigns each transponder a code and a corresponding chemical. After each chemical step, the IRORI machine uses radiofrequency communication to read the code (at the rate of ~1000/hour). This information is used to redirect the container to the next appropriate reaction.

"I remember when I first saw it I thought it was cute, but that it looked like a two-dollar solution to a two-cent problem," says Czarnik, who until recently was the vice-president for chemistry at IRORI. "But it is actually a very elegant solution to a problem that there aren’t obvious alternatives to."

IRORI’s next-generation tag is a 2D bar code: a patchwork of light and dark squares which is laser-etched on a ceramic surface, and then read by a camera. And a group at Pfizer, Inc. (Groton, Conn.) led by Eric Roskamp has developed a simple numbering system, which uses a heated printing press, graphite ink and optical character recognition.

A matrix for deconvolution.

For chemists who spurn beads and stick to the more traditional ways of solution chemistry, making and decoding mixtures is still a possibility. These decoding methods are collectively called deconvolution. One possibility is shown to the left, for a chemical made of two parts. In each mixture, one of the two positions is held constant, while the other is varied. The results from the first set of mixtures indicates the best chemical for part A, and the second set of mixtures gives the best part B. The chemists would then make the single chemical AB and test its properties.

Of course, if you do parallel synthesis you have none of these worries. As long as you keep track of each compound during all the chemical transformations you can deduce its final structure.

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