Understanding the basis of drug resistance of the mutants of αβ-tubulin dimer via molecular dynamics simulations.

The vital role of tubulin dimer in cell division makes it an attractive drug target. Drugs that target tubulin showed significant clinical success in treating various cancers. However, the efficacy of these drugs is attenuated by the emergence of tubulin mutants that are unsusceptible to several cla...

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Autores principales:	Kathiresan Natarajan, Sanjib Senapati
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e6efcdb11d2b48269175fa2b6239ddd0
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spelling	oai:doaj.org-article:e6efcdb11d2b48269175fa2b6239ddd02021-11-18T07:09:27ZUnderstanding the basis of drug resistance of the mutants of αβ-tubulin dimer via molecular dynamics simulations.1932-620310.1371/journal.pone.0042351https://doaj.org/article/e6efcdb11d2b48269175fa2b6239ddd02012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22879949/?tool=EBIhttps://doaj.org/toc/1932-6203The vital role of tubulin dimer in cell division makes it an attractive drug target. Drugs that target tubulin showed significant clinical success in treating various cancers. However, the efficacy of these drugs is attenuated by the emergence of tubulin mutants that are unsusceptible to several classes of tubulin binding drugs. The molecular basis of drug resistance of the tubulin mutants is yet to be unraveled. Here, we employ molecular dynamics simulations, protein-ligand docking, and MMPB(GB)SA analyses to examine the binding of anticancer drugs, taxol and epothilone to the reported point mutants of tubulin--T274I, R282Q, and Q292E. Results suggest that the mutations significantly alter the tubulin structure and dynamics, thereby weaken the interactions and binding of the drugs, primarily by modifying the M loop conformation and enlarging the pocket volume. Interestingly, these mutations also affect the tubulin distal sites that are associated with microtubule building processes.Kathiresan NatarajanSanjib SenapatiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 8, p e42351 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kathiresan Natarajan Sanjib Senapati Understanding the basis of drug resistance of the mutants of αβ-tubulin dimer via molecular dynamics simulations.
description	The vital role of tubulin dimer in cell division makes it an attractive drug target. Drugs that target tubulin showed significant clinical success in treating various cancers. However, the efficacy of these drugs is attenuated by the emergence of tubulin mutants that are unsusceptible to several classes of tubulin binding drugs. The molecular basis of drug resistance of the tubulin mutants is yet to be unraveled. Here, we employ molecular dynamics simulations, protein-ligand docking, and MMPB(GB)SA analyses to examine the binding of anticancer drugs, taxol and epothilone to the reported point mutants of tubulin--T274I, R282Q, and Q292E. Results suggest that the mutations significantly alter the tubulin structure and dynamics, thereby weaken the interactions and binding of the drugs, primarily by modifying the M loop conformation and enlarging the pocket volume. Interestingly, these mutations also affect the tubulin distal sites that are associated with microtubule building processes.
format	article
author	Kathiresan Natarajan Sanjib Senapati
author_facet	Kathiresan Natarajan Sanjib Senapati
author_sort	Kathiresan Natarajan
title	Understanding the basis of drug resistance of the mutants of αβ-tubulin dimer via molecular dynamics simulations.
title_short	Understanding the basis of drug resistance of the mutants of αβ-tubulin dimer via molecular dynamics simulations.
title_full	Understanding the basis of drug resistance of the mutants of αβ-tubulin dimer via molecular dynamics simulations.
title_fullStr	Understanding the basis of drug resistance of the mutants of αβ-tubulin dimer via molecular dynamics simulations.
title_full_unstemmed	Understanding the basis of drug resistance of the mutants of αβ-tubulin dimer via molecular dynamics simulations.
title_sort	understanding the basis of drug resistance of the mutants of αβ-tubulin dimer via molecular dynamics simulations.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/e6efcdb11d2b48269175fa2b6239ddd0
work_keys_str_mv	AT kathiresannatarajan understandingthebasisofdrugresistanceofthemutantsofabtubulindimerviamoleculardynamicssimulations AT sanjibsenapati understandingthebasisofdrugresistanceofthemutantsofabtubulindimerviamoleculardynamicssimulations
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Understanding the basis of drug resistance of the mutants of αβ-tubulin dimer via molecular dynamics simulations.

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