title: Use of peptide combinatorial libraries in drug design: the identification of a potent serotonin reuptake inhibitor derived from a tripeptide cassette library.
abstract: BACKGROUND
  Medicinal chemistry traditionally requires the identification of biologically active molecules by synthesizing and screening each purified substrate. Further progress in drug discovery then requires definition of the structure-activity relationship of the lead compound. More recently, combinatorial chemistry has emerged as a way to examine structure-activity relationships by screening a large mixture of compounds synthesized in a predictably random manner, without the labor-intensive costs of molecular isolation and purification. We set out to 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 inhibition using cloned transporter assay systems. The method has afforded a number of tripeptide pharmacophores with inhibitory IC50 values ranging from 10 microM to < 1 microM in the dopamine and serotonin reuptake systems. 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 microM) was compared to that of the serotonin uptake inhibitor s-fluoxetine, and was shown to be more similar in conformation to fluoxetine than was an analogous tripeptide containing L-Lys (IC50 > 50 microM).
  
  
  CONCLUSIONS
  We have identified five tripeptides with inhibitory IC50 values of < 10 microM in the serotonin reuptake system. One tripeptide was predicted to have pharmacophore features similar to that of fluoxetine, a selective and potent non-peptide serotonin reuptake inhibitor. Our results suggest that tripeptides derived from combinatorial libraries will help to define the important structural elements of pharmacophores.
authors.affiliation: CNS Division, Lilly Research Laboratories, Indianapolis, IN 46285, USA.
authors.forename: G
authors.initials: G
authors.lastname: Koppel
authors.forename: C
authors.initials: C
authors.lastname: Dodds
authors.forename: B
authors.initials: B
authors.lastname: Houchins
authors.forename: D
authors.initials: D
authors.lastname: Hunden
authors.forename: D
authors.initials: D
authors.lastname: Johnson
authors.forename: R
authors.initials: R
authors.lastname: Owens
authors.forename: M
authors.initials: M
authors.lastname: Chaney
authors.forename: T
authors.initials: T
authors.lastname: Usdin
authors.forename: B
authors.initials: B
authors.lastname: Hoffman
authors.forename: M
authors.initials: M
authors.lastname: Brownstein
mesh_terms: D000818:Animals; D018765:Dopamine Uptake Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D005473:Fluoxetine / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D018765:Dopamine Uptake Inhibitors; D005473:Fluoxetine; D009842:Oligopeptides; D017367:Selective Serotonin Reuptake Inhibitors