The Combinatorial Approach

There are two general approaches for finding the correct answer to a question (besides asking someone who knows). One way is to learn everything relevant to the topic and then to use your knowledge to arrive logically at the answer. Scientists, and most other people, almost always use this method. A second approach is to keep guessing until you've guessed right! This seems like a foolhardy strategy, and usually is. What if it took a million guesses before you stumbled upon the right answer? But what if you could make a million or a billion guesses all at once? Through combinatorial chemistry, scientists can make and test millions, billions, or even quadrillions (1015) of guesses about which chemical compound might have a desirable function, such as the ability to bind to a specific molecule, or to serve as a drug.

Many chemicals are pieced together through combinations of smaller building blocks. For example, benzene is a chemical consisting of six carbon atoms connected in an aromatic ring structure, with a hydrogen atom bound to each carbon. Substituting one of the hydrogens with a hydroxyl (-OH) group forms the chemical phenol. Substituting a methyl (-CH3) group instead forms toluene, and substituting an amino (-NH2) group forms aniline. Because of their different "functional groups," or side groups, all of these compounds have very different physical and chemical properties. More variations can be synthesized by substituting additional side groups with more than one of the hydrogens. By substituting one of just these three groups (or by not adding any groups) for any of the six hydrogens in a benzene ring, there are 46, or 4,096, possible combinations (the number of different compounds is much smaller, because benzene is symmetrical, and many of the combinations represent equivalent structures).

Side groups can also be placed onto other side groups. For example, a single chlorine atom can substitute for one of the hydrogens of the methyl group in toluene to form benzyl chloride. By using a moderately sized collection of side groups, placing them onto a "scaffold" molecule that is more complex than


The substitution of side groups on simple molecules can create many new molecules.

benzene (such as cholesterol, which has three six-carbon rings and a five-carbon ring), and by using additional levels of side groups, combinatorial chemists synthesize create can synthesize vast numbers of distinct but related compounds.

Although the utility of combinatorial chemistry was not fully appreciated by scientists until the 1980s, nature uses this strategy over and over. Genes, after all, are composed of different combinations of only four different nucleotides, and just twenty different amino acids form the building blocks of all proteins. In the immune systems of mammals, B lymphocytes use an elaborate scheme for mutating and combining different segments of antibody genes to generate a diverse pool of antibody molecules that can recognize and bind a wide array of alien molecules that enter the body with a pathogen infection.

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