{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T18:14:39Z","timestamp":1781892879429,"version":"3.54.5"},"reference-count":36,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T00:00:00Z","timestamp":1613692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["GR-2013-02355028"],"award-info":[{"award-number":["GR-2013-02355028"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Computer aided drug-design methods proved to be powerful tools for the identification of new therapeutic agents. We employed a structure-based workflow to identify new inhibitors targeting mTOR kinase at rapamycin binding site. By combining molecular dynamics (MD) simulation and pharmacophore modelling, a simplified structure-based pharmacophore hypothesis was built starting from the FKBP12-rapamycin-FRB ternary complex retrieved from RCSB Protein Data Bank (PDB code 1FAP). Then, the obtained model was used as filter to screen the ZINC biogenic compounds library, containing molecules derived from natural sources or natural-inspired compounds. The resulting hits were clustered according to their similarity; moreover, compounds showing the highest pharmacophore fit-score were chosen from each cluster. The selected molecules were subjected to docking studies to clarify their putative binding mode. The binding free energy of the obtained complexes was calculated by MM\/GBSA method and the hits characterized by the lowest \u0394Gbind values were identified as potential mTOR inhibitors. Furthermore, the stability of the resulting complexes was studied by means of MD simulation which revealed that the selected compounds were able to form a stable ternary complex with FKBP12 and FRB domain, thus underlining their potential ability to inhibit mTOR with a rapamycin-like mechanism.<\/jats:p>","DOI":"10.3390\/molecules26041103","type":"journal-article","created":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T20:54:08Z","timestamp":1613768048000},"page":"1103","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["In Silico Strategy for Targeting the mTOR Kinase at Rapamycin Binding Site by Small Molecules"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6092-5011","authenticated-orcid":false,"given":"Serena","family":"Vittorio","sequence":"first","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Palatucci 13, I-98168 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0002-2253","authenticated-orcid":false,"given":"Rosaria","family":"Gitto","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Palatucci 13, I-98168 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilenia","family":"Adornato","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Palatucci 13, I-98168 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1279-8123","authenticated-orcid":false,"given":"Emilio","family":"Russo","sequence":"additional","affiliation":[{"name":"Science of Health Department, School of Medicine, University \u201cMagna Graecia\u201d of Catanzaro, Viale Europa e Germaneto, I-88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0614-5713","authenticated-orcid":false,"given":"Laura","family":"De Luca","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Palatucci 13, I-98168 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.phrs.2016.03.039","article-title":"mTOR pathway inhibition as a new therapeutic strategy in epilepsy and epileptogenesis","volume":"107","author":"Citraro","year":"2016","journal-title":"Pharmacol. 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