The new method synthesizes many different compounds at once in complex mixtures. Then, because of the presence of a molecular target, its components naturally will evolve into the best candidate molecules.

"This method employs basic principles of Darwinian evolution," said Eliseev. "It's survival of the fittest. Our method increases the amount of the desirable compounds and decreases the amount of the undesirable ones."

Unlike other combinatorial methods, the UB method works by using molecular recognition -- the ability of molecules to bind to a target -- to simultaneously form and screen mixtures of many chemicals for the best ones.

During a stage the scientists call equilibration, or variation, the components of these mixtures are manipulated by the presence of the molecular target to "evolve" higher fractions of the best compounds.

"Our mixture circulates through two chromatographic columns," explained Eliseev. "In one of them, which we call the selection chamber, the effective components bind to the immobilized target compound. In the other one, the remaining mixture is brought to an equilibrium, where the mixture regenerates the fraction of the effective binders it just lost."

In the same way that natural evolution plays out over the course of many generations, chemical evolution occurs over the course of many repeated cycles during which the chemical library continually reforms itself, evolving a much larger subset of effective components.

These components then are isolated from the mixture and analyzed to identify potential drug leads.

The method has been proven in a model system.

The UB scientists are using it to develop drug candidates against the enzyme pepsin, which is found in the stomach and involved in the formation of ulcers.

'"/>

Contact: Ellen Goldbaum
goldbaum@newsb.buffalo.edu
716-645-2626
University at Buffalo
22-May-1998