title: Computational design and experimental discovery of an antiestrogenic peptide derived from alpha-fetoprotein.
abstract: Breast cancer is the most common cancer among women, and tamoxifen is the preferred drug for estrogen receptor-positive breast cancer treatment. Many of these cancers are intrinsically resistant to tamoxifen or acquire resistance during treatment. Consequently, there is an ongoing need for breast cancer drugs that have different molecular targets. Previous work has shown that 8-mer and cyclic 9-mer peptides inhibit breast cancer in mouse and rat models, interacting with an unsolved receptor, while peptides smaller than eight amino acids did not. We show that the use of replica exchange molecular dynamics predicts the structure and dynamics of active peptides, leading to the discovery of smaller peptides with full biological activity. Simulations identified smaller peptide analogues with the same conserved reverse turn demonstrated in the larger peptides. These analogues were synthesized and shown to inhibit estrogen-dependent cell growth in a mouse uterine growth assay, a test showing reliable correlation with human breast cancer inhibition.
authors: Hamilton College, Department of Chemistry, Center for Molecular Design, 198 College Hill Road, Clinton, New York 13323, USA.
authors: Karl N
authors: KN
authors: Kirschner
authors: Katrina W
authors: KW
authors: Lexa
authors: Amanda M
authors: AM
authors: Salisburg
authors: Katherine A
authors: KA
authors: Alser
authors: Leroy
authors: L
authors: Joseph
authors: Thomas T
authors: TT
authors: Andersen
authors: James A
authors: JA
authors: Bennett
authors: Herbert I
authors: HI
authors: Jacobson
authors: George C
authors: GC
authors: Shields
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015195:Drug Design; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D014599:Uterus / Q000187:drug effects; D000509:alpha-Fetoproteins / Q000737:chemistry*
chemical_list: D020847:Estrogen Receptor Modulators; D009842:Oligopeptides; D000509:alpha-Fetoproteins