{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T06:27:58Z","timestamp":1786343278279,"version":"build-2736575974"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioinform."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Peroxisome proliferator-activated receptor gamma (PPAR\u03b3) is a ligand-activated nuclear receptor with broad therapeutic relevance across various pathologies, including type 2 diabetes, obesity, cancer, and inflammatory disorders. Cannabinoids are a class of terpene-phenolic compounds from\n                      <jats:italic>Cannabis sativa<\/jats:italic>\n                      L. that have been shown to act as partial agonists of PPAR\u03b3. Among them, the acidic forms \u0394\n                      <jats:sup>9<\/jats:sup>\n                      -tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA) display higher potency than their decarboxylated counterp arts \u0394\n                      <jats:sup>9<\/jats:sup>\n                      -tetrahydrocannabinol (THC) and cannabidiol (CBD). Despite experimental evidence supporting direct PPAR\u03b3-cannabinoid interaction, the molecular determinants governing ligand recognition within the binding pocket have not yet been comprehensively investigated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A combination of molecular docking and molecular dynamics simulations was employed to characterize the binding modes of THC, CBD, THCA, and CBDA within the PPAR\u03b3 ligand-binding domain. Docking calculations were performed on a curated set of 70 PPAR\u03b3 crystal structures co-crystallized with structurally diverse ligands, exploiting thus the conformational variability of the binding pocket. The best-ranked solutions were subjected to 500 ns MD simulations and evaluated on the basis of ligand stability, persistence of polar and aromatic-aromatic interactions with the receptor, and energetic contributions estimated by MM\/GBSA. Three candidate binding modes per ligand were selected and their trajectories extended to 1,000 ns.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>All four cannabinoids yielded at least one stable binding mode at the microsecond timescale. The cannabinoids THCA and CBDA displayed a greater number of stable binding modes than THC and CBD, a result consistent with the higher potency previously reported for these compounds in experimental studies. This behavior may be attributable to the formation of salt bridges with basic residues in the binding pocket.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings provide a structural framework for understanding cannabinoid recognition by PPAR\u03b3. The ability of these compounds to adopt multiple binding modes may contribute to their partial agonist profile, opening new avenues for the rational design of selective PPAR\u03b3 modulators with improved therapeutic properties.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fbinf.2026.1893303","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T05:30:49Z","timestamp":1786339849000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Multiple binding modes underlie Cannabis sativa cannabinoids recognition by peroxisome proliferator-activated receptor gamma"],"prefix":"10.3389","volume":"6","author":[{"given":"N. R. Carina","family":"Alves","sequence":"first","affiliation":[{"name":"Departamento de Qu\u00edmica Biol\u00f3gica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria","place":["Buenos Aires, Argentina"]},{"name":"UMYMFOR, CONICET - Universidad de Buenos Aires, Ciudad Universitaria","place":["Buenos Aires, Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justina","family":"Miranda","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Biol\u00f3gica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria","place":["Buenos Aires, Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lautaro D.","family":"Alvarez","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Biol\u00f3gica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria","place":["Buenos Aires, Argentina"]},{"name":"UMYMFOR, CONICET - Universidad de Buenos Aires, Ciudad Universitaria","place":["Buenos Aires, Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3274","DOI":"10.1021\/acs.jmedchem.3c02391","article-title":"Structural basis for molecular recognition of cannabinoids by inhibitory Cys-loop channels","volume":"67","author":"Alvarez","year":"2024","journal-title":"J. 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