Isomer-sourced structure iteration methods for in silico development of inhibitors: Inducing GTP-bound NRAS-Q61 oncogenic mutations to an “off-like” state

The NRAS-mutant subset of melanoma represent some of the most aggressive and deadliest types associated with poor overall survival. Unfortunately, for more than 40 years, no therapeutic agent directly targeting NRAS mutations has been clinically approved. In this work, based on microsecond scale mol...

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Autores: Hu, Zheyao, Martí Rabassa, Jordi|||0000-0002-3721-9634
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Universitat Politècnica de Catalunya (UPC)
Repositorio:UPCommons. Portal del coneixement obert de la UPC
Idioma:inglés
OAI Identifier:oai:upcommons.upc.edu:2117/408734
Acceso en línea:https://hdl.handle.net/2117/408734
https://dx.doi.org/10.1016/j.csbj.2024.05.038
Access Level:acceso abierto
Palabra clave:Drugs--Design
Oncogenes
Molecular mechanisms
Drug design
NRAS oncogenes
ISSI method
HM-387 compound
Medicaments--Disseny
Oncogens
Àrees temàtiques de la UPC::Física
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network_acronym_str ES
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repository_id_str
spelling Isomer-sourced structure iteration methods for in silico development of inhibitors: Inducing GTP-bound NRAS-Q61 oncogenic mutations to an “off-like” stateHu, ZheyaoMartí Rabassa, Jordi|||0000-0002-3721-9634Drugs--DesignOncogenesMolecular mechanismsDrug designNRAS oncogenesISSI methodHM-387 compoundMedicaments--DissenyOncogensÀrees temàtiques de la UPC::FísicaThe NRAS-mutant subset of melanoma represent some of the most aggressive and deadliest types associated with poor overall survival. Unfortunately, for more than 40 years, no therapeutic agent directly targeting NRAS mutations has been clinically approved. In this work, based on microsecond scale molecular dynamics simulations, the effect of Q61 mutations on NRAS conformational characteristics is revealed at the atomic level. The GTP-bound NRAS-Q61R and Q61K mutations show a specific targetable pocket between Switch-II and a-helix 3 whereas the NRAS-Q61L non-polar mutation category shows a different targetable pocket. Moreover, a new isomer-sourced structure iteration method has been developed for the in silico design of a potential inhibitor prototype (HM-387) capable of targeting NRAS-Q61R proteins. We also show the possibility of HM-387 targeting activated NRAS-Q61R and that it can gradually induce the transition of an activated NRAS-Q61R to an “off-like” state.Elsevier20242024-05-2420242024-05-28journal articlehttp://purl.org/coar/resource_type/c_6501AMhttp://purl.org/coar/version/c_ab4af688f83e57aainfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/2117/408734https://dx.doi.org/10.1016/j.csbj.2024.05.038reponame:UPCommons. Portal del coneixement obert de la UPCinstname:Universitat Politècnica de Catalunya (UPC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:upcommons.upc.edu:2117/4087342026-05-27T15:37:01Z
dc.title.none.fl_str_mv Isomer-sourced structure iteration methods for in silico development of inhibitors: Inducing GTP-bound NRAS-Q61 oncogenic mutations to an “off-like” state
title Isomer-sourced structure iteration methods for in silico development of inhibitors: Inducing GTP-bound NRAS-Q61 oncogenic mutations to an “off-like” state
spellingShingle Isomer-sourced structure iteration methods for in silico development of inhibitors: Inducing GTP-bound NRAS-Q61 oncogenic mutations to an “off-like” state
Hu, Zheyao
Drugs--Design
Oncogenes
Molecular mechanisms
Drug design
NRAS oncogenes
ISSI method
HM-387 compound
Medicaments--Disseny
Oncogens
Àrees temàtiques de la UPC::Física
title_short Isomer-sourced structure iteration methods for in silico development of inhibitors: Inducing GTP-bound NRAS-Q61 oncogenic mutations to an “off-like” state
title_full Isomer-sourced structure iteration methods for in silico development of inhibitors: Inducing GTP-bound NRAS-Q61 oncogenic mutations to an “off-like” state
title_fullStr Isomer-sourced structure iteration methods for in silico development of inhibitors: Inducing GTP-bound NRAS-Q61 oncogenic mutations to an “off-like” state
title_full_unstemmed Isomer-sourced structure iteration methods for in silico development of inhibitors: Inducing GTP-bound NRAS-Q61 oncogenic mutations to an “off-like” state
title_sort Isomer-sourced structure iteration methods for in silico development of inhibitors: Inducing GTP-bound NRAS-Q61 oncogenic mutations to an “off-like” state
dc.creator.none.fl_str_mv Hu, Zheyao
Martí Rabassa, Jordi|||0000-0002-3721-9634
author Hu, Zheyao
author_facet Hu, Zheyao
Martí Rabassa, Jordi|||0000-0002-3721-9634
author_role author
author2 Martí Rabassa, Jordi|||0000-0002-3721-9634
author2_role author
dc.subject.none.fl_str_mv Drugs--Design
Oncogenes
Molecular mechanisms
Drug design
NRAS oncogenes
ISSI method
HM-387 compound
Medicaments--Disseny
Oncogens
Àrees temàtiques de la UPC::Física
topic Drugs--Design
Oncogenes
Molecular mechanisms
Drug design
NRAS oncogenes
ISSI method
HM-387 compound
Medicaments--Disseny
Oncogens
Àrees temàtiques de la UPC::Física
description The NRAS-mutant subset of melanoma represent some of the most aggressive and deadliest types associated with poor overall survival. Unfortunately, for more than 40 years, no therapeutic agent directly targeting NRAS mutations has been clinically approved. In this work, based on microsecond scale molecular dynamics simulations, the effect of Q61 mutations on NRAS conformational characteristics is revealed at the atomic level. The GTP-bound NRAS-Q61R and Q61K mutations show a specific targetable pocket between Switch-II and a-helix 3 whereas the NRAS-Q61L non-polar mutation category shows a different targetable pocket. Moreover, a new isomer-sourced structure iteration method has been developed for the in silico design of a potential inhibitor prototype (HM-387) capable of targeting NRAS-Q61R proteins. We also show the possibility of HM-387 targeting activated NRAS-Q61R and that it can gradually induce the transition of an activated NRAS-Q61R to an “off-like” state.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024-05-24
2024
2024-05-28
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
AM
http://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/2117/408734
https://dx.doi.org/10.1016/j.csbj.2024.05.038
url https://hdl.handle.net/2117/408734
https://dx.doi.org/10.1016/j.csbj.2024.05.038
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:UPCommons. Portal del coneixement obert de la UPC
instname:Universitat Politècnica de Catalunya (UPC)
instname_str Universitat Politècnica de Catalunya (UPC)
reponame_str UPCommons. Portal del coneixement obert de la UPC
collection UPCommons. Portal del coneixement obert de la UPC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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