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Targeted Drug Discovery: Targeting a Specific Conformation of MutS/MSH Proteins with Small Molecules

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abstract
Mismatch repair proteins repair mismatches in the DNA and signal cell death in response to certain DNA lesions. Due to these distinct functions of MMR proteins, they are proposed to exist in at least two different conformations, "repair" and "death." The goal of this study was to exploit the structural aspects of the "death" conformation to identify small molecules that will interact with MSH2/MSH6 and induce MMR-dependent damage signaling pathway that has been shown to be p53- and ATM-independent. Utilizing molecular dynamics simulations and autodocking experiments, databases were searched for commercially available compounds that preferentially bind the "death" conformation of MSH2/MSH6. Reserpine and its derivative rescinnamine were identified, both compounds previously used in the treatment of hypertension. Reserpine and rescinnamine decrease cell viability and activate caspase 3 cleavage in a MSH2- and MSH6-dependent manner. In addition, rescinnamine inhibits tumor growth in a dose-dependent manner in in vivo pilot studies.
subject
cancer
mismatch repair
MSH
MutS
small molecules
contributor
Vasilyeva, Aksana (author)
Scarpinato, Karin D (committee chair)
Kucera, Gregory L (committee member)
Berquin, Isabelle (committee member)
Cramer, Scott D (committee member)
Hollis, Thomas (committee member)
date
2011-02-16T21:42:19Z (accessioned)
2011-09-29T08:30:13Z (available)
2010 (issued)
degree
Cancer Biology (discipline)
embargo
2011-09-29 (terms)
identifier
http://hdl.handle.net/10339/30403 (uri)
language
en (iso)
publisher
Wake Forest University
title
Targeted Drug Discovery: Targeting a Specific Conformation of MutS/MSH Proteins with Small Molecules
type
Dissertation

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