A common pharmacophore for a diverse set of colchicine site inhibitors using a structure-based approach

Nguyen, TL and McGrath, C and Hermone, AR and Burnett, JC and Zaharevitz, DW and Day, BW and Wipf, P and Hamel, E and Gussio, R (2005) A common pharmacophore for a diverse set of colchicine site inhibitors using a structure-based approach. Journal of Medicinal Chemistry, 48 (19). 6107 - 6116. ISSN 0022-2623

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Abstract

Modulating the structure and function of tubulin and microtubules is an important route to anticancer therapeutics, and therefore, small molecules that bind to tubulin and cause mitotic arrest are of immense interest. A large number of synthetic and natural compounds with diverse structures have been shown to bind at the colchicine site, one of the major binding sites on tubulin, and inhibit tubulin assembly. Using the recently determined X-ray structure of the tubulin:colchicinoid complex as the template, we employed docking studies to determine the binding modes of a set of structurally diverse colchicine site inhibitors. These binding models were subsequently used to construct a comprehensive, structure-based pharmacophore that in combination with molecular dynamics simulations confirms and extends our understanding of binding interactions at the colchicine site. © 2005 American Chemical Society.

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Nguyen, TL McGrath, C Hermone, AR Burnett, JC Zaharevitz, DW Day, BW Wipf, P pwipf@pitt.edu PWIPF Hamel, E Gussio, R
Date:	22 September 2005
Date Type:	Publication
Journal or Publication Title:	Journal of Medicinal Chemistry
Volume:	48
Number:	19
Page Range:	6107 - 6116
DOI or Unique Handle:	10.1021/jm050502t
Schools and Programs:	Dietrich School of Arts and Sciences > Chemistry
Refereed:	Yes
ISSN:	0022-2623
MeSH Headings:	4-Butyrolactone--analogs & derivatives; 4-Butyrolactone--chemistry; Aminophenols--chemistry; Binding Sites; Chalcone--chemistry; Colchicine--chemistry; Cyclopropanes--chemistry; Estradiol--analogs & derivatives; Estradiol--chemistry; Indans--chemistry; Lignans--chemistry; Models, Molecular; Molecular Structure; Nocodazole--chemistry; Podophyllotoxin--chemistry; Protein Binding; Stilbenes--chemistry; Structure-Activity Relationship; Sulfonamides--chemistry; Thiazoles--chemistry; Tubulin--chemistry; Tubulin Modulators
PubMed ID:	16162011
Date Deposited:	31 Oct 2013 18:13
Last Modified:	05 Feb 2019 12:55
URI:	http://d-scholarship-dev.library.pitt.edu/id/eprint/19948

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