{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T07:24:37Z","timestamp":1782631477991,"version":"3.54.5"},"reference-count":61,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,9,7]],"date-time":"2025-09-07T00:00:00Z","timestamp":1757203200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The mammalian target of rapamycin pathway, mTOR, is a crucial signaling pathway that regulates cell growth, proliferation, metabolism, and survival. Due to its dysregulation it is involved in several ailments such as cancer or age-related diseases. The discovery of mTOR and the understanding of its biological functions were greatly facilitated by the use of rapamycin, an antibiotic of natural origin, which allosterically inhibits mTORC1, effectively blocking its function. In this entirely computational study, we investigated mTOR\u2019s interaction with seven ligands: two clinically established inhibitors (everolimus and rapamycin) and five lignin-derived oligomers, a renewable natural polyphenol recently used for the drug delivery of everolimus. The seven complexes were analyzed through all-atom molecular dynamics simulations in explicit solvent using a high-performance computing platform. Trajectory analyses revealed stable interactions between mTOR and all ligands, with lignin-derived compounds showing comparable or enhanced binding stability relative to reference drugs. To evaluate the stability of the molecular complex and the behavior of the ligand over time, we analyzed key parameters including root mean square deviation, root mean square fluctuation, number of hydrogen bonds, binding free energy, and conformational dynamics assessed through principal component analysis. Our results suggest that lignin fragments are a promising, sustainable scaffold for developing novel mTOR inhibitors.<\/jats:p>","DOI":"10.3390\/ijms26178728","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T10:27:12Z","timestamp":1757500032000},"page":"8728","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Lignin-Derived Oligomers as Promising mTOR Inhibitors: Insights from Dynamics Simulations"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1311-3082","authenticated-orcid":false,"given":"Sofia","family":"Gabellone","sequence":"first","affiliation":[{"name":"IRCCS Istituto Romagnolo per lo Studio dei Tumori \u201cDino Amadori\u201d\u2014IRST Srl, 47014 Meldola, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5328-4683","authenticated-orcid":false,"given":"Giovanni","family":"Carotenuto","sequence":"additional","affiliation":[{"name":"Department of Ecological and Biological Sciences, Tuscia University, Viale dell\u2019Universit\u00e0 s.n.c., 01100 Viterbo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2312-7704","authenticated-orcid":false,"given":"Manuel","family":"Arcieri","sequence":"additional","affiliation":[{"name":"Department of Computer Science, \u201cSapienza\u201d University of Rome, V. le Regina Elena 295, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4662-2019","authenticated-orcid":false,"given":"Paolo","family":"Bottoni","sequence":"additional","affiliation":[{"name":"Department of Computer Science, \u201cSapienza\u201d University of Rome, V. le Regina Elena 295, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6141-1572","authenticated-orcid":false,"given":"Giulia","family":"Sbanchi","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Romagnolo per lo Studio dei Tumori \u201cDino Amadori\u201d\u2014IRST Srl, 47014 Meldola, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0689-6720","authenticated-orcid":false,"given":"Tiziana","family":"Castrignan\u00f2","sequence":"additional","affiliation":[{"name":"Department of Ecological and Biological Sciences, Tuscia University, Viale dell\u2019Universit\u00e0 s.n.c., 01100 Viterbo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6561-2222","authenticated-orcid":false,"given":"Davide","family":"Piccinino","sequence":"additional","affiliation":[{"name":"Department of Ecological and Biological Sciences, Tuscia University, Viale dell\u2019Universit\u00e0 s.n.c., 01100 Viterbo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4279-1926","authenticated-orcid":false,"given":"Chiara","family":"Liverani","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Romagnolo per lo Studio dei Tumori \u201cDino Amadori\u201d\u2014IRST Srl, 47014 Meldola, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4420-9063","authenticated-orcid":false,"given":"Raffaele","family":"Saladino","sequence":"additional","affiliation":[{"name":"Department of Ecological and Biological Sciences, Tuscia University, Viale dell\u2019Universit\u00e0 s.n.c., 01100 Viterbo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s12154-008-0003-5","article-title":"Rapamycin and mTOR kinase inhibitors","volume":"1","author":"Ballou","year":"2008","journal-title":"J. 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