Computational analysis of ELOVL6 structure and inhibition for rational drug design

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dc.contributor.authorIbarluzea, Markel G.
dc.contributor.authorRamis Cortés, Rafael
dc.contributor.authorFuentetaja, Martín
dc.contributor.authorGil Bea, Francisco Javier
dc.contributor.authorGereñu Lopetegi, Gorka
dc.contributor.authorLópez de Munain Arregui, Adolfo
dc.contributor.authorAizpurua Iparraguirre, Jesus Mari
dc.contributor.authorMiranda, Jose I.
dc.contributor.authorBergara, Aitor
dc.contributor.authorLeonardo, Aritz
dc.date.accessioned2026-08-05T08:13:43Z
dc.date.available2026-08-05T08:13:43Z
dc.date.issued2026-06-05
dc.date.updated2026-08-05T08:13:43Z
dc.description.abstractELOVL6 is a key enzyme in long-chain fatty acid elongation, catalyzing the conversion of C16 fatty acids into C18 fatty acids. While its role in lipid metabolism is well established, recent studies have linked ELOVL6 to metabolic and neurodegenerative diseases, making it an attractive therapeutic target. However, the absence of a resolved crystal structure and limited mechanistic understanding of its inhibition pose significant challenges for drug discovery. In this study, we employ a multitiered computational approach, including structure prediction, molecular dynamics (MD) simulations, and free energy calculations, to investigate the structural basis of ELOVL6 function and inhibition. We identify the most thermodynamically favorable substrate binding pathway and characterize key conformational changes associated with ligand binding. By analyzing potential inhibitor binding pockets, we determine that known inhibitors preferentially target the active site, and we validate their binding affinities against experimental data. Additionally, by comparing ELOVL6 with homologous elongases, we pinpoint potentially key amino acid residues responsible for selectivity, providing insights that could guide structure-based drug design. Our findings establish a mechanistic framework for rational inhibitor development, offering a foundation for future efforts in optimizing ELOVL6-targeting therapeutics.en
dc.description.sponsorshipMarkel G. Ibarluzea, Rafael Ramis, Martin Fuentetaja, Aitor Bergara, and Aritz Leonardo acknowledge financial support from the Spanish Ministry of Science and Innovation (Grant No. PID2022-139230NB-I00), the Department of Education, Universities, and Research of the Basque Government, the University of the Basque Country (Grant No. IT1707-22), and the Department of Health of the Basque Government (Grant No. 2025333026)en
dc.identifier.citationIbarluzea, M. G., Ramis, R., Fuentetaja, M., Gil-Bea, F. J., Gerenu, G., López De Munain, A., Aizpurua, J. M., Miranda, J. I., Bergara, A., & Leonardo, A. (2026). Computational analysis of ELOVL6 structure and inhibition for rational drug design. Journal of Chemical Information and Modeling, 66(12), 7264-7275. https://doi.org/10.1021/ACS.JCIM.6C00336
dc.identifier.doi10.1021/ACS.JCIM.6C00336
dc.identifier.eissn1549-960X
dc.identifier.issn1549-9596
dc.identifier.urihttps://hdl.handle.net/20.500.14454/6470
dc.language.isoeng
dc.publisherAmerican Chemical Society
dc.titleComputational analysis of ELOVL6 structure and inhibition for rational drug designen
dc.typejournal article
dcterms.accessRightsopen access
oaire.citation.endPage7275
oaire.citation.issue12
oaire.citation.startPage7264
oaire.citation.titleJournal of Chemical Information and Modeling
oaire.citation.volume66
oaire.licenseConditionhttps://creativecommons.org/licenses/by/4.0/
oaire.versionVoR
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