Virtual and biophysical screening targeting the γ-tubulin complex--a new target for the inhibition of microtubule nucleation.

Microtubules are the main constituents of mitotic spindles. They are nucleated in large amounts during spindle assembly, from multiprotein complexes containing γ-tubulin and associated γ-tubulin complex proteins (GCPs). With the aim of developing anti-cancer drugs targeting these nucleating complexe...

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Autores principales:	Olivier Cala, Marie-Hélène Remy, Valérie Guillet, Andreas Merdes, Lionel Mourey, Alain Milon, Georges Czaplicki
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/75705f809df6439785004efd0ffb3743
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spelling	oai:doaj.org-article:75705f809df6439785004efd0ffb37432021-11-18T07:45:38ZVirtual and biophysical screening targeting the γ-tubulin complex--a new target for the inhibition of microtubule nucleation.1932-620310.1371/journal.pone.0063908https://doaj.org/article/75705f809df6439785004efd0ffb37432013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23691113/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Microtubules are the main constituents of mitotic spindles. They are nucleated in large amounts during spindle assembly, from multiprotein complexes containing γ-tubulin and associated γ-tubulin complex proteins (GCPs). With the aim of developing anti-cancer drugs targeting these nucleating complexes, we analyzed the interface between GCP4 and γ-tubulin proteins usually located in a multiprotein complex named γ-TuRC (γ-Tubulin Ring Complex). 10 ns molecular dynamics simulations were performed on the heterodimers to obtain a stable complex in silico and to analyze the residues involved in persistent protein-protein contacts, responsible for the stability of the complex. We demonstrated in silico the existence of a binding pocket at the interface between the two proteins upon complex formation. By combining virtual screening using a fragment-based approach and biophysical screening, we found several small molecules that bind specifically to this pocket. Sub-millimolar fragments have been experimentally characterized on recombinant proteins using differential scanning fluorimetry (DSF) for validation of these compounds as inhibitors. These results open a new avenue for drug development against microtubule-nucleating γ-tubulin complexes.Olivier CalaMarie-Hélène RemyValérie GuilletAndreas MerdesLionel MoureyAlain MilonGeorges CzaplickiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 5, p e63908 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Olivier Cala Marie-Hélène Remy Valérie Guillet Andreas Merdes Lionel Mourey Alain Milon Georges Czaplicki Virtual and biophysical screening targeting the γ-tubulin complex--a new target for the inhibition of microtubule nucleation.
description	Microtubules are the main constituents of mitotic spindles. They are nucleated in large amounts during spindle assembly, from multiprotein complexes containing γ-tubulin and associated γ-tubulin complex proteins (GCPs). With the aim of developing anti-cancer drugs targeting these nucleating complexes, we analyzed the interface between GCP4 and γ-tubulin proteins usually located in a multiprotein complex named γ-TuRC (γ-Tubulin Ring Complex). 10 ns molecular dynamics simulations were performed on the heterodimers to obtain a stable complex in silico and to analyze the residues involved in persistent protein-protein contacts, responsible for the stability of the complex. We demonstrated in silico the existence of a binding pocket at the interface between the two proteins upon complex formation. By combining virtual screening using a fragment-based approach and biophysical screening, we found several small molecules that bind specifically to this pocket. Sub-millimolar fragments have been experimentally characterized on recombinant proteins using differential scanning fluorimetry (DSF) for validation of these compounds as inhibitors. These results open a new avenue for drug development against microtubule-nucleating γ-tubulin complexes.
format	article
author	Olivier Cala Marie-Hélène Remy Valérie Guillet Andreas Merdes Lionel Mourey Alain Milon Georges Czaplicki
author_facet	Olivier Cala Marie-Hélène Remy Valérie Guillet Andreas Merdes Lionel Mourey Alain Milon Georges Czaplicki
author_sort	Olivier Cala
title	Virtual and biophysical screening targeting the γ-tubulin complex--a new target for the inhibition of microtubule nucleation.
title_short	Virtual and biophysical screening targeting the γ-tubulin complex--a new target for the inhibition of microtubule nucleation.
title_full	Virtual and biophysical screening targeting the γ-tubulin complex--a new target for the inhibition of microtubule nucleation.
title_fullStr	Virtual and biophysical screening targeting the γ-tubulin complex--a new target for the inhibition of microtubule nucleation.
title_full_unstemmed	Virtual and biophysical screening targeting the γ-tubulin complex--a new target for the inhibition of microtubule nucleation.
title_sort	virtual and biophysical screening targeting the γ-tubulin complex--a new target for the inhibition of microtubule nucleation.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/75705f809df6439785004efd0ffb3743
work_keys_str_mv	AT oliviercala virtualandbiophysicalscreeningtargetingthegtubulincomplexanewtargetfortheinhibitionofmicrotubulenucleation AT marieheleneremy virtualandbiophysicalscreeningtargetingthegtubulincomplexanewtargetfortheinhibitionofmicrotubulenucleation AT valerieguillet virtualandbiophysicalscreeningtargetingthegtubulincomplexanewtargetfortheinhibitionofmicrotubulenucleation AT andreasmerdes virtualandbiophysicalscreeningtargetingthegtubulincomplexanewtargetfortheinhibitionofmicrotubulenucleation AT lionelmourey virtualandbiophysicalscreeningtargetingthegtubulincomplexanewtargetfortheinhibitionofmicrotubulenucleation AT alainmilon virtualandbiophysicalscreeningtargetingthegtubulincomplexanewtargetfortheinhibitionofmicrotubulenucleation AT georgesczaplicki virtualandbiophysicalscreeningtargetingthegtubulincomplexanewtargetfortheinhibitionofmicrotubulenucleation
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Virtual and biophysical screening targeting the γ-tubulin complex--a new target for the inhibition of microtubule nucleation.

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