Exploratory Covalent Docking of Michael-Acceptor Natural Products at Reactive Cysteines in Cancer Tyrosine Kinases

This article belongs to the Section Molecular Oncology

Bibliographic Details
Authors: Lobo, Fernando, Pérez de la Lastra, José Manuel, Curieses Andrés, Celia María, Bustamante Munguira, Elena, Andrés Juan, Celia, Pérez-Lebeña, Eduardo
Format: article
Status:Published version
Publication Date:2025
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/408535
Online Access:http://hdl.handle.net/10261/408535
Access Level:Open access
Keyword:Cancer
Tyrosine kinases
Covalent docking
Covalent inhibitors
Michael-acceptor
Natural products
Reactive cysteine
AutoDockFR
EGFR
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spelling Exploratory Covalent Docking of Michael-Acceptor Natural Products at Reactive Cysteines in Cancer Tyrosine KinasesLobo, FernandoPérez de la Lastra, José ManuelCurieses Andrés, Celia MaríaBustamante Munguira, ElenaAndrés Juan, CeliaPérez-Lebeña, EduardoCancerTyrosine kinasesCovalent dockingCovalent inhibitorsMichael-acceptorNatural productsReactive cysteineAutoDockFREGFRThis article belongs to the Section Molecular OncologyTyrosine kinases (TKs) and cyclin-dependent kinases (CDKs) contain reactive cysteines that can be exploited by targeted covalent inhibitors. In this exploratory computational study, we asked whether selected natural-product-like (NP-like) electrophiles bearing Michael-acceptor (MA) motifs could adopt geometries consistent with covalent approaches to these cysteines, in a manner analogous to approved covalent TKIs. Using AutoDockFR with cysteine-centered grids and explicit side-chain flexibility, we performed pocket-focused, within-receptor covalent docking for EGFR, VEGFR2/KDR, PDGFRβ (via PDGFRα surrogate), BTK, CDK7, and CDK12. Reference inhibitors (osimertinib–EGFR, ibrutinib–BTK, THZ1–CDK7, and THZ531–CDK12) reproduced the expected geometries and served as internal controls. NP-like electrophiles (parthenolide, withaferin A, celastrol, and curcumin as a low-reactivity geometry probe) displayed pocket-compatible orientations in several targets, particularly EGFR and BTK, suggesting feasible pre-reaction alignment toward the reactive cysteine. Although no quantitative affinity was inferred, the consistent geometric feasibility supports their potential as structural templates for covalent-binding natural scaffolds. These results provide a qualitative, structure-based rationale for further chemoproteomic and enzymatic validation of NP-derived or hybrid compounds as potential leads in cancer therapy, expanding covalent chemical space beyond existing synthetic scaffolds.Peer reviewedMultidisciplinary Digital Publishing InstitutePérez de la Lastra, José Manuel [0000-0003-4663-5565]Curieses Andrés, Celia María [0000-0003-4731-6398]Andrés Juan, Celia [0000-0003-1583-7439]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2025202520252025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/408535reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésThe underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.3390/ijms262311390https://doi.org/10.3390/ijms262311390Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/4085352026-05-22T06:33:51Z
dc.title.none.fl_str_mv Exploratory Covalent Docking of Michael-Acceptor Natural Products at Reactive Cysteines in Cancer Tyrosine Kinases
title Exploratory Covalent Docking of Michael-Acceptor Natural Products at Reactive Cysteines in Cancer Tyrosine Kinases
spellingShingle Exploratory Covalent Docking of Michael-Acceptor Natural Products at Reactive Cysteines in Cancer Tyrosine Kinases
Lobo, Fernando
Cancer
Tyrosine kinases
Covalent docking
Covalent inhibitors
Michael-acceptor
Natural products
Reactive cysteine
AutoDockFR
EGFR
title_short Exploratory Covalent Docking of Michael-Acceptor Natural Products at Reactive Cysteines in Cancer Tyrosine Kinases
title_full Exploratory Covalent Docking of Michael-Acceptor Natural Products at Reactive Cysteines in Cancer Tyrosine Kinases
title_fullStr Exploratory Covalent Docking of Michael-Acceptor Natural Products at Reactive Cysteines in Cancer Tyrosine Kinases
title_full_unstemmed Exploratory Covalent Docking of Michael-Acceptor Natural Products at Reactive Cysteines in Cancer Tyrosine Kinases
title_sort Exploratory Covalent Docking of Michael-Acceptor Natural Products at Reactive Cysteines in Cancer Tyrosine Kinases
dc.creator.none.fl_str_mv Lobo, Fernando
Pérez de la Lastra, José Manuel
Curieses Andrés, Celia María
Bustamante Munguira, Elena
Andrés Juan, Celia
Pérez-Lebeña, Eduardo
author Lobo, Fernando
author_facet Lobo, Fernando
Pérez de la Lastra, José Manuel
Curieses Andrés, Celia María
Bustamante Munguira, Elena
Andrés Juan, Celia
Pérez-Lebeña, Eduardo
author_role author
author2 Pérez de la Lastra, José Manuel
Curieses Andrés, Celia María
Bustamante Munguira, Elena
Andrés Juan, Celia
Pérez-Lebeña, Eduardo
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Pérez de la Lastra, José Manuel [0000-0003-4663-5565]
Curieses Andrés, Celia María [0000-0003-4731-6398]
Andrés Juan, Celia [0000-0003-1583-7439]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Cancer
Tyrosine kinases
Covalent docking
Covalent inhibitors
Michael-acceptor
Natural products
Reactive cysteine
AutoDockFR
EGFR
topic Cancer
Tyrosine kinases
Covalent docking
Covalent inhibitors
Michael-acceptor
Natural products
Reactive cysteine
AutoDockFR
EGFR
description This article belongs to the Section Molecular Oncology
publishDate 2025
dc.date.none.fl_str_mv 2025
2025
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/408535
url http://hdl.handle.net/10261/408535
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.3390/ijms262311390
https://doi.org/10.3390/ijms262311390
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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