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The search for low energy conformational families of small peptides: Searching for active conformations of small peptides in the absence of a known receptor
Author(s) -
Lexa Katrina W.,
Alser Katherine A.,
Salisburg Amanda M.,
Ellens Damien J.,
Hernandez Lorena,
Bono Sam J.,
Michael Heather C.,
Derby Jennifer R.,
Skiba Jaime G.,
Feldgus Steven,
Kirschner Karl N.,
Shields George C.
Publication year - 2007
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.21449
Subject(s) - tamoxifen , breast cancer , estrogen receptor , molecular dynamics , cancer , peptide , chemistry , amino acid , estrogen receptor alpha , cancer research , computational biology , biology , biochemistry , genetics , computational chemistry
Breast cancer is the most common cancer among women. Tamoxifen is the preferred drug for estrogen receptor‐positive breast cancer treatment, yet many of these cancers are intrinsically resistant to tamoxifen or acquire resistance during treatment. Therefore, scientists are searching for breast cancer drugs that have different molecular targets. Previous work revealed that 8‐mer and cyclic 9‐mer peptides inhibit breast cancer in mouse and rat model systems, interacting with an unknown receptor, while peptides smaller than eight amino acids did not inhibit breast cancer. We have shown that the use of replica exchange molecular dynamics predicts structure and dynamics of active peptides, leading to the discovery of smaller peptides with full biological activity. These simulations identified smaller peptide analogs with a conserved turn, a β‐turn formed in the larger peptides. These analogs inhibit estrogen‐dependent cell growth in a mouse uterine growth assay, a test showing reliable correlation with human breast cancer inhibition. We outline the computational methods that were tried and used with the experimental information that led to the successful completion of this research. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2007