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Despite advances in antiseizure medications (ASMs), challenges persist, particularly drug resistance and significant psychiatric and behavioral adverse effects. Isoguvacine (IGV), a potent \u03b3-aminobutyric acid type A receptor agonist, holds promise for epilepsy treatment but suffers from poor blood\u2013brain barrier (BBB) permeability due to its zwitterionic nature. To address this limitation, two ester prodrugs:\n                    <jats:bold>E7<\/jats:bold>\n                    (heptyl 1,2,3,6-tetrahydropyridine-4-carboxylate) and\n                    <jats:bold>E14<\/jats:bold>\n                    (tetradecyl 1,2,3,6-tetrahydropyridine-4-carboxylate) were synthesized to enhance BBB penetration and central nervous system (CNS) delivery. This study investigates the interactions of IGV and its derivatives with human serum albumin (HSA), a key plasma transport protein, using a suite of biophysical and computational techniques. UV spectroscopic analysis confirmed protein\u2013ligand complexation, with\n                    <jats:bold>E7<\/jats:bold>\n                    and\n                    <jats:bold>E14<\/jats:bold>\n                    exhibiting enhanced binding compared to IGV. Isothermal titration calorimetry revealed that\n                    <jats:bold>E14<\/jats:bold>\n                    demonstrated superior binding affinity (\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>a<\/jats:italic>\n                    <\/jats:sub>\n                    = 2.42\u2009\u00d7\u200910\n                    <jats:sup>6<\/jats:sup>\n                    M\u207b\u00b9) compared to\n                    <jats:bold>E7<\/jats:bold>\n                    (\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>a<\/jats:italic>\n                    <\/jats:sub>\n                    = 3.41\u2009\u00d7\u200910\n                    <jats:sup>4<\/jats:sup>\n                    M\u207b\u00b9), while IGV showed negligible interaction. Atomic force microscopy and circular dichroism spectroscopy indicated that the enhanced hydrophobicity of\n                    <jats:bold>E7<\/jats:bold>\n                    and\n                    <jats:bold>E14<\/jats:bold>\n                    promoted stable protein\u2013ligand interactions without perturbing the secondary and tertiary structures of HSA. Molecular docking studies corroborated the superior binding affinity of\n                    <jats:bold>E14<\/jats:bold>\n                    towards HSA, while molecular dynamics simulations confirmed the enhanced stability of the\n                    <jats:bold>E14<\/jats:bold>\n                    \u2013HSA complex. These results highlight the potential of\n                    <jats:bold>E14<\/jats:bold>\n                    as a promising prodrug candidate for CNS-targeted epilepsy therapy and underscore the importance of albumin binding in modulating drug bioavailability and distribution.\n                  <\/jats:p>","DOI":"10.1038\/s41598-025-25957-7","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T15:58:54Z","timestamp":1764086334000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Improved albumin binding properties of Isoguvacine upon esterification as characterized by biophysical and computational tools"],"prefix":"10.1038","volume":"15","author":[{"given":"Yan Hong","family":"Ng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhamad Imam","family":"Muhajir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rani","family":"Maharani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Unang","family":"Supratman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jalifah","family":"Latip","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Murni Nazira","family":"Sarian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Su Datt","family":"Lam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shevin Rizal","family":"Feroz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"25957_CR1","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1097\/01.NME.0000559583.43254.ab","volume":"17","author":"A Perkins","year":"2019","unstructured":"Perkins, A. 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