USE OF PEPTIDE COMBINATORIAL LIBRARIES IN DRUG DESIGN - THE IDENTIFICATION OF A POTENT SEROTONIN REUPTAKE INHIBITOR DERIVED FROM A TRIPEPTIDE CASSETTE LIBRARY

Background: Medicinal chemistry traditionally requires the identificat ion of biologically active molecules by synthesizing and screening eac h purified substrate. Further progress in drug discovery then requires definition of the structure-activity relationship of the lead compoun d. More recently, combinatorial chemistry has emerged as a way to exam ine structure-activity relationships by screening a large mixture of c ompounds synthesized in a predictably random manner, without the labor -intensive costs of molecular isolation and purification. We set out t o use this approach to examine the structural requirements for peptide binding to serotonin and dopamine transporters. Results: We screened a tripeptide cassette library for serotonin and dopamine reuptake inhi bition using cloned transporter assay systems. The method has afforded a number of tripeptide pharmacophores with inhibitory IC50 values ran ging from 10 mu M to < 1 mu M in the dopamine and serotonin reuptake s ystems. The conformation of one of these tripeptides, N-acetyl-D-Trp-L -Phe-D-Lys-CONH2 (which inhibits serotonin uptake with an IC50 of 10 m u M) was compared to that of the serotonin uptake inhibitor s-fluoxeti ne, and was shown to be more similar in conformation to fluoxetine tha n was an analogous tripeptide containing L-Lys (IC50 > 50 mu M). Concl usions: We have identified five tripeptides with inhibitory IC50 value s of < 10 mu M in the serotonin reuptake system. One tripeptide was pr edicted to have pharmacophore features similar to that of fluoxetine, a selective and potent non-peptide serotonin reuptake inhibitor. Our r esults suggest that tripeptides derived from combinatorial libraries w ill help to define the important structural elements of pharmacophores .