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Statistical analysis of data from molecular dynamics simulations is performed to quantify the suitability of the ligands as constituents of active targeting drug delivery systems. The preferred binding modes of each ligand are identified and discussed in terms of ligand positioning and mechanism of binding. Interaction maps and structures of representative clusters highlight the key amino acid residues involved in the ligand\u2013receptor complexes and provide clues for the attachment mechanism of the ligands. The results reveal that the complex formation is primarily driven by dispersion forces, particularly involving the pterin and aminobenzoate fragments, with additional stabilization from hydrogen bonds and electrostatics. Specific interaction patterns are identified for each ligand, which provide rationalization of the experimentally registered dissimilar behavior of the studied vectors toward the receptor. On the basis of the performed analyses, general guidelines for ligands to bind to the active site of the protein are formulated. Among the addressed ligands, only folate and raltitrexed comply with the requirements and bind sustainably to the receptor active site, outlining them as effective vectors for folate-based drug-delivery systems.<\/jats:p>","DOI":"10.1021\/acs.jpcb.6c02404","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T14:03:25Z","timestamp":1785852205000},"page":"8200-8211","source":"Crossref","is-referenced-by-count":0,"title":["Specificity of\nthe Interactions of Folate-Based Vectors\nwith Folate Receptor-\u03b1"],"prefix":"10.1021","volume":"130","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4593-9834","authenticated-orcid":true,"given":"Jasmina","family":"Petkova","sequence":"first","affiliation":[{"name":"Sofia University \u201cSt. Kliment Ohridski\u201d , , 1 James Bourchier Blvd , ,","place":["Sofia, Bulgaria, 1164"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galia","family":"Madjarova","sequence":"additional","affiliation":[{"name":"Sofia University \u201cSt. Kliment Ohridski\u201d , , 1 James Bourchier Blvd , ,","place":["Sofia, Bulgaria, 1164"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Vasilaki","sequence":"additional","affiliation":[{"name":"Sofia University \u201cSt. Kliment Ohridski\u201d , , 1 James Bourchier Blvd , ,","place":["Sofia, Bulgaria, 1164"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gergana","family":"Gocheva","sequence":"additional","affiliation":[{"name":"Sofia University \u201cSt. Kliment Ohridski\u201d , , 1 James Bourchier Blvd , ,","place":["Sofia, Bulgaria, 1164"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1655-8327","authenticated-orcid":true,"given":"Nikoleta","family":"Ivanova","sequence":"additional","affiliation":[{"name":"Sofia University \u201cSt. Kliment Ohridski\u201d , , 1 James Bourchier Blvd , ,","place":["Sofia, Bulgaria, 1164"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stoyan","family":"Iliev","sequence":"additional","affiliation":[{"name":"Sofia University \u201cSt. Kliment Ohridski\u201d , , 1 James Bourchier Blvd , ,","place":["Sofia, Bulgaria, 1164"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6220-7961","authenticated-orcid":true,"given":"Anela","family":"Ivanova","sequence":"additional","affiliation":[{"name":"Sofia University \u201cSt. Kliment Ohridski\u201d , , 1 James Bourchier Blvd , ,","place":["Sofia, Bulgaria, 1164"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"2026081308075764200_cit1","doi-asserted-by":"publisher","first-page":"1959","DOI":"10.1080\/10717544.2022.2089296","article-title":"Functional ligands\nfor improving anticancer drug therapy: Current status and applications\nto drug delivery systems","volume":"29","author":"Bajracharya","year":"2022","journal-title":"Drug Delivery"},{"issue":"1","key":"2026081308075764200_cit2","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/s41392-017-0004-3","article-title":"Controlled drug delivery\nvehicles for cancer treatment and their performance","volume":"3","author":"Senapati","year":"2018","journal-title":"Signal Transduction Targeted Ther."},{"key":"2026081308075764200_cit3","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.2147\/IJN.S289443","article-title":"Nanocarriers-mediated\ndrug delivery systems for anticancer agents: An overview and perspectives","volume":"16","author":"Edis","year":"2021","journal-title":"Int. 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Pharmacol."},{"key":"2026081308075764200_cit42","doi-asserted-by":"publisher","first-page":"2","DOI":"10.2174\/1573394718666220508181053","article-title":"Recent\nupdates on folate targeted\ndrug delivery systems in cancer: A mini review","volume":"19","author":"Sharma","year":"2023","journal-title":"Curr. 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