How Does the L884P Mutation Confer Resistance to Type-II Inhibitors of JAK2 Kinase: A Comprehensive Molecular Modeling Study

Abstract Janus kinase 2 (JAK2) has been regarded as an essential target for the treatment of myeloproliferative neoplasms (MPNs). BBT594 and CHZ868, Type-II inhibitors of JAK2, illustrate satisfactory efficacy in preclinical MPNs and acute lymphoblastic leukemia (ALL) models. However, the L884P muta...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Xiaotian Kong, Huiyong Sun, Peichen Pan, Dan Li, Feng Zhu, Shan Chang, Lei Xu, Youyong Li, Tingjun Hou
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/03cf48cea5864341a8f24ed238c7bd07
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:03cf48cea5864341a8f24ed238c7bd07
record_format	dspace
spelling	oai:doaj.org-article:03cf48cea5864341a8f24ed238c7bd072021-12-02T12:32:17ZHow Does the L884P Mutation Confer Resistance to Type-II Inhibitors of JAK2 Kinase: A Comprehensive Molecular Modeling Study10.1038/s41598-017-09586-32045-2322https://doaj.org/article/03cf48cea5864341a8f24ed238c7bd072017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-09586-3https://doaj.org/toc/2045-2322Abstract Janus kinase 2 (JAK2) has been regarded as an essential target for the treatment of myeloproliferative neoplasms (MPNs). BBT594 and CHZ868, Type-II inhibitors of JAK2, illustrate satisfactory efficacy in preclinical MPNs and acute lymphoblastic leukemia (ALL) models. However, the L884P mutation of JAK2 abrogates the suppressive effects of BBT594 and CHZ868. In this study, conventional molecular dynamics (MD) simulations, umbrella sampling (US) simulations and MM/GBSA free energy calculations were employed to explore how the L884P mutation affects the binding of BBT594 and CHZ868 to JAK2 and uncover the resistance mechanism induced by the L884P mutation. The results provided by the US and MD simulations illustrate that the L884P mutation enhances the flexibility of the allosteric pocket and alters their conformations, which amplify the conformational entropy change (−TΔS) and weaken the interactions between the inhibitors and target. Additionally, the structural analyses of BBT594 and CHZ868 in complex with the WT JAK2 illustrate that the drug tail with strong electronegativity and small size located in the allosteric pocket of JAK2 may enhance anti-resistance capability. In summary, our results highlight that both of the changes of the conformational entropies and enthalpies contribute to the L884P-induced resistance in the binding of two Type-II inhibitors into JAK2 kinase.Xiaotian KongHuiyong SunPeichen PanDan LiFeng ZhuShan ChangLei XuYouyong LiTingjun HouNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Xiaotian Kong Huiyong Sun Peichen Pan Dan Li Feng Zhu Shan Chang Lei Xu Youyong Li Tingjun Hou How Does the L884P Mutation Confer Resistance to Type-II Inhibitors of JAK2 Kinase: A Comprehensive Molecular Modeling Study
description	Abstract Janus kinase 2 (JAK2) has been regarded as an essential target for the treatment of myeloproliferative neoplasms (MPNs). BBT594 and CHZ868, Type-II inhibitors of JAK2, illustrate satisfactory efficacy in preclinical MPNs and acute lymphoblastic leukemia (ALL) models. However, the L884P mutation of JAK2 abrogates the suppressive effects of BBT594 and CHZ868. In this study, conventional molecular dynamics (MD) simulations, umbrella sampling (US) simulations and MM/GBSA free energy calculations were employed to explore how the L884P mutation affects the binding of BBT594 and CHZ868 to JAK2 and uncover the resistance mechanism induced by the L884P mutation. The results provided by the US and MD simulations illustrate that the L884P mutation enhances the flexibility of the allosteric pocket and alters their conformations, which amplify the conformational entropy change (−TΔS) and weaken the interactions between the inhibitors and target. Additionally, the structural analyses of BBT594 and CHZ868 in complex with the WT JAK2 illustrate that the drug tail with strong electronegativity and small size located in the allosteric pocket of JAK2 may enhance anti-resistance capability. In summary, our results highlight that both of the changes of the conformational entropies and enthalpies contribute to the L884P-induced resistance in the binding of two Type-II inhibitors into JAK2 kinase.
format	article
author	Xiaotian Kong Huiyong Sun Peichen Pan Dan Li Feng Zhu Shan Chang Lei Xu Youyong Li Tingjun Hou
author_facet	Xiaotian Kong Huiyong Sun Peichen Pan Dan Li Feng Zhu Shan Chang Lei Xu Youyong Li Tingjun Hou
author_sort	Xiaotian Kong
title	How Does the L884P Mutation Confer Resistance to Type-II Inhibitors of JAK2 Kinase: A Comprehensive Molecular Modeling Study
title_short	How Does the L884P Mutation Confer Resistance to Type-II Inhibitors of JAK2 Kinase: A Comprehensive Molecular Modeling Study
title_full	How Does the L884P Mutation Confer Resistance to Type-II Inhibitors of JAK2 Kinase: A Comprehensive Molecular Modeling Study
title_fullStr	How Does the L884P Mutation Confer Resistance to Type-II Inhibitors of JAK2 Kinase: A Comprehensive Molecular Modeling Study
title_full_unstemmed	How Does the L884P Mutation Confer Resistance to Type-II Inhibitors of JAK2 Kinase: A Comprehensive Molecular Modeling Study
title_sort	how does the l884p mutation confer resistance to type-ii inhibitors of jak2 kinase: a comprehensive molecular modeling study
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/03cf48cea5864341a8f24ed238c7bd07
work_keys_str_mv	AT xiaotiankong howdoesthel884pmutationconferresistancetotypeiiinhibitorsofjak2kinaseacomprehensivemolecularmodelingstudy AT huiyongsun howdoesthel884pmutationconferresistancetotypeiiinhibitorsofjak2kinaseacomprehensivemolecularmodelingstudy AT peichenpan howdoesthel884pmutationconferresistancetotypeiiinhibitorsofjak2kinaseacomprehensivemolecularmodelingstudy AT danli howdoesthel884pmutationconferresistancetotypeiiinhibitorsofjak2kinaseacomprehensivemolecularmodelingstudy AT fengzhu howdoesthel884pmutationconferresistancetotypeiiinhibitorsofjak2kinaseacomprehensivemolecularmodelingstudy AT shanchang howdoesthel884pmutationconferresistancetotypeiiinhibitorsofjak2kinaseacomprehensivemolecularmodelingstudy AT leixu howdoesthel884pmutationconferresistancetotypeiiinhibitorsofjak2kinaseacomprehensivemolecularmodelingstudy AT youyongli howdoesthel884pmutationconferresistancetotypeiiinhibitorsofjak2kinaseacomprehensivemolecularmodelingstudy AT tingjunhou howdoesthel884pmutationconferresistancetotypeiiinhibitorsofjak2kinaseacomprehensivemolecularmodelingstudy
_version_	1718394076766666752

How Does the L884P Mutation Confer Resistance to Type-II Inhibitors of JAK2 Kinase: A Comprehensive Molecular Modeling Study

Ejemplares similares