First let’s refresh our memories as to the basic technique behind synthesis by
combinatorial chemistry: this is outlined here using, for purely illustrative purposes,
a 3 x 3 array of reaction cells, i.e. nine cells:
3-Iodopropanoic acid is converted to the methyl, ethyl, and propyl esters, by
effecting across row 1 methylation, across row 2 ethylation, and across row 3
propylation. Then the esters are converted to fluoro-, chloro, and bromo-compounds
by appropriate substitution reactions down columns 1, 2, and 3. In practice a 10 x 10 or
bigger array might be used, creating 100 or more different compounds. The procedure
can be automated and carried out on a small “microchip” (“lab on a chip”). One would
likely begin with a compound that showed to some extent the desired activity, and
make a host of variants. This relatively quick synthesis of many drug candidates,
followed by mass testing, is called high-throughput screening (HTS).
There has been some disappointment with combinatorial chemistry. This is
discussed in a nicely balanced article with the engaging cover title “I, chemist.
Researchers trump robots in drug discovery” (shades of Isaac Asimov!) [1]. It
appears that the method may have been oversold; indeed, a cynic might say that
with millions of compounds generated by combinatorial chemistry, we should now
have effective drugs for all diseases. HTS does continue to be useful: “Most sources
agree that combinatorial chemistry is an important part of building a library of
compounds from which to work and that HTS is needed at some point in the process
of drug discovery.” [1]. Nevertheless, if we realize that all diseases are molecular,
we are led to conclude that if our understanding of the mechanisms by which
chemical processes cause disease is sufficiently sophisticated, then rational mole-
cular intervention should be the most effective approach to drug therapy. As Dror
Ofer of Keddem Bioscience was quoted as saying [1]: “The real issue in drug
discovery is that we don’t understand the key steps in developing a drug. We must
say this openly and clearly. To understand, in science, means only one thing: the
ability to predict results. Medicinal chemists must study physical chemistry – how
atoms really react to one another. You have to go back to the science when
something doesn’t work, rather than applying more brute force.”
Reference
- Mullin R (2004) Chemical and Engineering News,26 July, p 23
Chapter 1, Harder Questions, Answers
Q10
Think up some unusual molecule which might be investigated computationally.
What is it that makes your molecule unusual?
Answers 593