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Peer-reviewedCC BY 4.0Biomolecules

Receptor-Specific Molecular Recognition of Maresin 1 and Docosahexaenoic Acid by the Nuclear Receptors PPARα, PPARγ, and RORα

  • Matías Quiñones San Martín1,2
  • Christian Olivera-Fuentes2,3
  • Francisca Herrera-Vielma1
  • Ramón Norambuena-González1,4
  • Eduardo Solís-Céspedes5
  • Daniel R. González1
  • Yunier Perera-Sardiña1
  • Jessica Zúñiga-Hernández1
5 affiliations
  1. 1Laboratory of Pharmacology and Physiology, Department of Basic Biomedical Sciences, Faculty of Health Sciences, University of Talca, Talca 3460000, Chile
  2. 2Doctorate in Science Program, Mention in Research and Development of Bioactive Products, Institute of Chemistry of Natural Resources, University of Talca, Talca 3460000, Chile
  3. 3Laboratory of Molecular Physiology, Faculty of Medicine, University of Talca, Talca 3460000, Chile
  4. 4Doctorate in Biomedical Sciences Program, Faculty of Health Sciences, University of Talca, Talca 3460000, Chile
  5. 5Department of Preclinical Sciences, Faculty of Medicine, Catholic University of Maule, Talca 3460000, Chile
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Abstract

Background/Objectives: Maresin 1 (MaR1), a pro-resolving mediator derived from docosahexaenoic acid (DHA), differs from DHA in its C7/C14 hydroxylation pattern and double-bond arrangement. We compared their recognition by peroxisome proliferator-activated receptor α (PPARα), peroxisome proliferator-activated receptor γ (PPARγ), and retinoic acid receptor-related orphan receptor α (RORα) in the context of metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: We validated Glide docking by redocking reference ligands and performed four independent 250 ns molecular dynamics simulations per complex (24 trajectories; 6.0 μs). We evaluated structural stability, replica-resolved contacts, oxygen distance profiles, and conformational sampling; relative energetic estimates were obtained using molecular mechanics/generalized Born surface area (MM-GBSA) calculations. Results: Redocking RMSDs were ≤1.5 Å, and the replicated trajectories showed no ligand dissociation. In PPARα, MaR1 showed recurrent C7-OH–Lys358 proximity and reproducible carboxylate-associated contacts with Tyr314 and Ser280. In PPARγ, the MaR1 carboxylate sampled Tyr473 in helix 12 and HIE323 with replica-dependent geometry, whereas DHA retained an Arg288-centered anchor. In RORα, MaR1 preferentially sampled an Arg370-centered arrangement, whereas DHA predominantly engaged Arg367; both ligands displayed replica-dependent alternative polar contacts. MaR1 showed more negative hydrogen-bonding, lipophilic, and van der Waals contributions and lower numerical total MM-GBSA scores than DHA across all three receptor pairs. Conclusions: MaR1 showed receptor-specific redistribution of polar contacts associated with alternative carboxylate positioning. Although the calculations do not establish binding affinity or receptor activation, these patterns, rather than a conserved direct C7-OH/C14-OH recognition motif, define testable interaction sites for matched-analog studies and functional assays.

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Cite

BibTeXRIS
BibTeX
@article{martin2026receptorspecific,
  title = {{Receptor-Specific Molecular Recognition of Maresin 1 and Docosahexaenoic Acid by the Nuclear Receptors PPARα, PPARγ, and RORα}},
  author = {Matías Quiñones San Martín and Christian Olivera-Fuentes and Francisca Herrera-Vielma and Ramón Norambuena-González and Eduardo Solís-Céspedes and Daniel R. González and Yunier Perera-Sardiña and Jessica Zúñiga-Hernández},
  journal = {Biomolecules},
  year = {2026},
  month = oct,
  doi = {10.3390/biom16111558},
  url = {https://www.mdpi.com/2218-273X/16/11/1558},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Receptor-Specific Molecular Recognition of Maresin 1 and Docosahexaenoic Acid by the Nuclear Receptors PPARα, PPARγ, and RORα
AU  - Matías Quiñones San Martín
AU  - Christian Olivera-Fuentes
AU  - Francisca Herrera-Vielma
AU  - Ramón Norambuena-González
AU  - Eduardo Solís-Céspedes
AU  - Daniel R. González
AU  - Yunier Perera-Sardiña
AU  - Jessica Zúñiga-Hernández
PY  - 2026
DA  - 2026/10/26
JO  - Biomolecules
DO  - 10.3390/biom16111558
UR  - https://www.mdpi.com/2218-273X/16/11/1558
AB  - Background/Objectives: Maresin 1 (MaR1), a pro-resolving mediator derived from docosahexaenoic acid (DHA), differs from DHA in its C7/C14 hydroxylation pattern and double-bond arrangement. We compared their recognition by peroxisome proliferator-activated receptor α (PPARα), peroxisome proliferator-activated receptor γ (PPARγ), and retinoic acid receptor-related orphan receptor α (RORα) in the context of metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: We validated Glide docking by redocking reference ligands and performed four independent 250 ns molecular dynamics simulations per complex (24 trajectories; 6.0 μs). We evaluated structural stability, replica-resolved contacts, oxygen distance profiles, and conformational sampling; relative energetic estimates were obtained using molecular mechanics/generalized Born surface area (MM-GBSA) calculations. Results: Redocking RMSDs were ≤1.5 Å, and the replicated trajectories showed no ligand dissociation. In PPARα, MaR1 showed recurrent C7-OH–Lys358 proximity and reproducible carboxylate-associated contacts with Tyr314 and Ser280. In PPARγ, the MaR1 carboxylate sampled Tyr473 in helix 12 and HIE323 with replica-dependent geometry, whereas DHA retained an Arg288-centered anchor. In RORα, MaR1 preferentially sampled an Arg370-centered arrangement, whereas DHA predominantly engaged Arg367; both ligands displayed replica-dependent alternative polar contacts. MaR1 showed more negative hydrogen-bonding, lipophilic, and van der Waals contributions and lower numerical total MM-GBSA scores than DHA across all three receptor pairs. Conclusions: MaR1 showed receptor-specific redistribution of polar contacts associated with alternative carboxylate positioning. Although the calculations do not establish binding affinity or receptor activation, these patterns, rather than a conserved direct C7-OH/C14-OH recognition motif, define testable interaction sites for matched-analog studies and functional assays.
SN  - 2218-273X
ER  -