Drug Targets

Combinatorial chemistry is most often used to synthesize "small molecules," in contrast to macromolecules such as DNA, RNA, proteins, and polysaccharides, which are polymers containing long chains of monomer subunits. Because of their enormous size, macromolecules cannot easily enter cells, which is an important requirement for compounds intended for use as drugs.

In many cases the combinatorial chemist is looking for a compound that will bind tightly and specifically to a cellular molecule, such as the catalytic, or "active," site on the inside of an enzyme. Small molecules can fit into the holes and crevasses leading to the active site. By binding the enzyme, the synthetic compound may prevent it from binding to its natural substrate or from carrying out its catalytic reaction. Defective enzymes that resist normal cellular restraints on their activities are responsible for many diseases, including certain cancers. Chemical inhibitors of such rogue enzymes hold promise as powerful drugs. Alternatively, binding of a small molecule to an enzyme could enhance the enzyme's normal activity. Such molecules have potential as drugs for diseases caused by insufficient activity of a crucial enzyme.

For two molecules to bind to one another, they must have a proper fit, like a key in a lock. The fit depends on the shapes of the two molecules as well as on the chemical interactions between them. For example, two positively charged side groups will repel each other, but negative and positive groups can attract. Not surprisingly, a synthetic compound that binds a particular molecule often has chemical properties and a shape mimicking the natural ligand for the molecule. Such compounds are termed analogues.

When the drug target is known, its structure can be used as a template to create analogues with complementary shapes. Alternatively, if an analogue is already in hand that binds the target but has undesirable properties (such as weak binding, poor solubility, or serious side effects), this structure can be used as a starting point. Even without such clues, the speed and automation of the combinatorial approach makes it feasible to randomly synthesize and test millions of compounds.

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